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Wood, Kris Cameron

Positions:

Assistant Professor of Pharmacology & Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Core Faculty in Innovation & Entrepreneurship

Duke Innovation & Entrepreneurship
Institutes and Provost's Academic Units

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

B.S. 2002

B.S. — University of Kentucky at Lexington

Ph.D. 2007

Ph.D. — Massachusetts Institute of Technology

News:

Grants:

Targeting tumor-specific apoptosis regulation in advanced ER+ breast cancer

Administered By
Pharmacology & Cancer Biology
AwardedBy
Department of Defense
Role
Principal Investigator
Start Date
August 15, 2019
End Date
August 14, 2022

Medical Scientist Training Program

Administered By
School of Medicine
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 1997
End Date
June 30, 2022

University Training Program in Biomolecular and Tissue Engineering

Administered By
Biomedical Engineering
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 1994
End Date
June 30, 2022

University Training Program in Biomolecular and Tissue Engineering

Administered By
Biomedical Engineering
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 1994
End Date
June 30, 2022

Computational Structure-Based Protein Design Non-competing Renewal (Yr. 10)

Administered By
Computer Science
AwardedBy
National Institutes of Health
Role
Collaborating Investigator
Start Date
April 15, 2008
End Date
April 30, 2022

Selectively targeting apoptosis in PIK3CA mutant colorectal cancers

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
August 12, 2016
End Date
July 31, 2021

Selectively targeting apoptosis in PIK3CA mutant colorectal cancers

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
August 12, 2016
End Date
July 31, 2021

Decoding human genetic variation by functional dissection of beta2-adrenergic receptor signaling

Administered By
Pharmacology & Cancer Biology
AwardedBy
American Heart Association
Role
Collaborating Investigator
Start Date
July 01, 2019
End Date
June 30, 2021

Codon bias imposes a targetable limitation on KRAS-driven therapeutic resistance

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 01, 2017
End Date
June 30, 2021

Codon bias imposes a targetable limitation on KRAS-driven therapeutic resistance

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 01, 2017
End Date
June 30, 2021

Determining the Sub-Cellular Organelles that Link Lipid Signaling and Epigenetics

Administered By
Sarah Stedman Nutrition & Metabolism Center
AwardedBy
National Institutes of Health
Role
Significant Contributor
Start Date
June 01, 2019
End Date
May 31, 2021

High-throughput screening of arrayed single cells for automated analysis of phenotypic heterogeneity

Administered By
Mechanical Engineering and Materials Science
Role
Co Investigator
Start Date
October 02, 2018
End Date
October 01, 2020

Mechanisms of immune checkpoint resistance mediated by LKB1 tumor suppressor in lung cancer

Administered By
Pharmacology & Cancer Biology
AwardedBy
Department of Defense
Role
Mentor
Start Date
July 15, 2019
End Date
July 14, 2020

Bioinformatics and Computational Biology Training Program

Administered By
Basic Science Departments
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 2005
End Date
June 30, 2020

Genetics Training Grant

Administered By
Basic Science Departments
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 01, 1979
End Date
June 30, 2020

Genetics Training Grant

Administered By
Basic Science Departments
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 01, 1979
End Date
June 30, 2020

Organization and Function of Cellular Structure

Administered By
Basic Science Departments
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 1975
End Date
June 30, 2020

Organization and Function of Cellular Structure

Administered By
Basic Science Departments
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 1975
End Date
June 30, 2020

Pharmacological Sciences Training Program

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Institutes of Health
Role
Participating Faculty Member
Start Date
July 01, 1975
End Date
June 30, 2020

Topological Methods for Morphology: Classifying Shape and Function via Dictionary Learning

Administered By
Statistical Science
AwardedBy
Columbia University
Role
Co-Principal Investigator
Start Date
May 01, 2016
End Date
April 30, 2020

Single cell functional dissection of tumor microenviornment-driven drug resistance

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
February 01, 2018
End Date
January 31, 2020

Precision targeting of altered mitochondrial states in ovarian cancer

Administered By
Pharmacology & Cancer Biology
Role
Principal Investigator
Start Date
February 01, 2015
End Date
January 31, 2020

Pharmacology Industry Internships for Ph.D. Students

Administered By
Pharmacology & Cancer Biology
AwardedBy
American Society for Pharmacology and Experimental Therapeutics
Role
Participating Faculty Member
Start Date
January 01, 2017
End Date
December 31, 2019

Targeting the Hippo pathway in Ras-driven rhabdomyosarcoma

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
V Foundation for Cancer Research
Role
Collaborator
Start Date
November 01, 2016
End Date
October 31, 2019

Targeting differential apoptosis regulation in triple negative breast cancer

Administered By
Pharmacology & Cancer Biology
AwardedBy
Department of Defense
Role
Principal Investigator
Start Date
September 30, 2016
End Date
September 29, 2019

Identification and validation of the PAX3-FOXO1 protein interactome

Administered By
Pediatrics, Hematology-Oncology
Role
Collaborator
Start Date
July 01, 2018
End Date
June 30, 2019

Identification of synthetic lethal interactors in pancreatic cancer

Administered By
Pharmacology & Cancer Biology
AwardedBy
University of North Carolina - Chapel Hill
Role
Principal Investigator
Start Date
September 01, 2015
End Date
June 30, 2019

Exploring BCL-XL addiction in pancreatic ductal adenocarcinoma

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 01, 2016
End Date
March 31, 2019

RalA signal transduction

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
February 01, 2002
End Date
March 31, 2019

Copy Number Alterations in Low Mutation Cancer

Administered By
Neurology
AwardedBy
National Institutes of Health
Role
Co-Mentor
Start Date
March 01, 2018
End Date
February 28, 2019

Exploiting collateral sensitivity to target kinase inhibitor-resistant lung cancers

Administered By
Pharmacology & Cancer Biology
AwardedBy
Burroughs Wellcome Fund
Role
Principal Investigator
Start Date
November 01, 2017
End Date
October 31, 2018

Unmasking targetable dependencies in cancer with intrinsic or acquired resistance to anti-cancer therapies

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 15, 2017
End Date
October 31, 2018

Integration of signaling and metabolic pathways in the regulation of EMT

Administered By
Pharmacology & Cancer Biology
Role
Principal Investigator
Start Date
October 01, 2016
End Date
September 30, 2018

Profiling Gene Interactions in the Human Kinome

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Science Foundation
Role
Principal Investigator
Start Date
September 01, 2015
End Date
August 31, 2018

Targeting undruggable oncogenes through the epigenome

Administered By
Pharmacology & Cancer Biology
Role
Principal Investigator
Start Date
June 09, 2017
End Date
June 08, 2018

Designing durable apoptosis-targeting therapies for acute myeloid leukemia

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
May 01, 2016
End Date
April 30, 2018

Mapping the landscape of drug sensitizers in human cancers

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
March 01, 2015
End Date
September 30, 2017

Genomic and Computational Approaches for Development of Novel Anticancer Therapies

Administered By
Pharmacology & Cancer Biology
Role
Principal Investigator
Start Date
August 23, 2015
End Date
August 31, 2017

Systematic design of CDK4/6 inhibitor-based combination therapies

Administered By
Pharmacology & Cancer Biology
Role
Principal Investigator
Start Date
April 01, 2015
End Date
October 28, 2016

A Platform for Real-time Drug Profiling of Patient-Derived Melanomas

Administered By
Surgery
AwardedBy
National Institutes of Health
Role
Co-Sponsor
Start Date
August 01, 2014
End Date
July 31, 2016

Cancer Biology Training Grant

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Cancer Institute
Role
Mentor
Start Date
July 01, 1993
End Date
March 31, 2016

Systematic dissection of the breast cancer microenvironment using the MicroSCALE Toolkit

Administered By
Pharmacology & Cancer Biology
AwardedBy
V Foundation for Cancer Research
Role
Principal Investigator
Start Date
December 01, 2013
End Date
November 30, 2015
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Publications:

Label propagation defines signaling networks associated with recurrently mutated cancer genes.

Human tumors have distinct profiles of genomic alterations, and each of these alterations has the potential to cause unique changes to cellular homeostasis. Detailed analyses of these changes could reveal downstream effects of genomic alterations, contributing to our understanding of their roles in tumor development and progression. Across a range of tumor types, including bladder, lung, and endometrial carcinoma, we determined genes that are frequently altered in The Cancer Genome Atlas patient populations, then examined the effects of these alterations on signaling and regulatory pathways. To achieve this, we used a label propagation-based methodology to generate networks from gene expression signatures associated with defined mutations. Individual networks offered a large-scale view of signaling changes represented by gene signatures, which in turn reflected the scope of molecular events that are perturbed in the presence of a given genomic alteration. Comparing different networks to one another revealed common biological pathways impacted by distinct genomic alterations, highlighting the concept that tumors can dysregulate key pathways through multiple, seemingly unrelated mechanisms. Finally, altered genes inducing common changes to the signaling network were used to search for genomic markers of drug response, connecting shared perturbations to differential drug sensitivity.

Authors
Cakir, M; Mukherjee, S; Wood, KC
MLA Citation
Cakir, Merve, et al. “Label propagation defines signaling networks associated with recurrently mutated cancer genes..” Sci Rep, vol. 9, no. 1, June 2019. Pubmed, doi:10.1038/s41598-019-45603-3.
PMID
31253832
Source
pubmed
Published In
Scientific Reports
Volume
9
Issue
1
Publish Date
2019
Start Page
9401
DOI
10.1038/s41598-019-45603-3

Systematic Dissection of the Metabolic-Apoptotic Interface in AML Reveals Heme Biosynthesis to Be a Regulator of Drug Sensitivity.

Crosstalk between metabolic and survival pathways is critical for cellular homeostasis, but the connectivity between these processes remains poorly defined. We used loss-of-function CRISPR/Cas9 knockout screening to identify metabolic genes capable of influencing cellular commitment to apoptosis, using sensitization to the BCL-2 inhibitor ABT-199 in BCL-2-dependent acute myeloid leukemia (AML) cell lines as a proxy for apoptotic disposition. This analysis revealed metabolic pathways that specifically cooperate with BCL-2 to sustain survival. In particular, our analysis singled out heme biosynthesis as an unappreciated apoptosis-modifying pathway. Although heme is broadly incorporated into the proteome, reduction of heme biosynthesis potentiates apoptosis through the loss of ETC activity, resulting in baseline depolarization of the mitochondrial membrane and an increased propensity to undergo apoptosis. Collectively, our findings chart the first apoptotic map of metabolism, motivating the design of metabolically engaged combination chemotherapies and nominating heme biosynthesis as an apoptotic modulator in AML.

Authors
Lin, KH; Xie, A; Rutter, JC; Ahn, Y-R; Lloyd-Cowden, JM; Nichols, AG; Soderquist, RS; Koves, TR; Muoio, DM; MacIver, NJ; Lamba, JK; Pardee, TS; McCall, CM; Rizzieri, DA; Wood, KC
MLA Citation
Lin, Kevin H., et al. “Systematic Dissection of the Metabolic-Apoptotic Interface in AML Reveals Heme Biosynthesis to Be a Regulator of Drug Sensitivity..” Cell Metab, vol. 29, no. 5, May 2019, pp. 1217-1231.e7. Pubmed, doi:10.1016/j.cmet.2019.01.011.
PMID
30773463
Source
pubmed
Published In
Cell Metab
Volume
29
Issue
5
Publish Date
2019
Start Page
1217
End Page
1231.e7
DOI
10.1016/j.cmet.2019.01.011

Pharmacodynamic study of radium-223 in men with bone metastatic castration resistant prostate cancer.

BACKGROUND: Radium-223 is a targeted alpha-particle therapy that improves survival in men with metastatic castration resistant prostate cancer (mCRPC), particularly in men with elevated serum levels of bone alkaline phosphatase (B-ALP). We hypothesized that osteomimicry, a form of epithelial plasticity leading to an osteoblastic phenotype, may contribute to intralesional deposition of radium-223 and subsequent irradiation of the tumor microenvironment. METHODS: We conducted a pharmacodynamic study (NCT02204943) of radium-223 in men with bone mCRPC. Prior to and three and six months after radium-223 treatment initiation, we collected CTCs and metastatic biopsies for phenotypic characterization and CTC genomic analysis. The primary objective was to describe the impact of radium-223 on the prevalence of CTC B-ALP over time. We measured radium-223 decay products in tumor and surrounding normal bone during treatment. We validated genomic findings in a separate independent study of men with bone metastatic mCRPC (n = 45) and publicly accessible data of metastatic CRPC tissues. RESULTS: We enrolled 20 men with symptomatic bone predominant mCRPC and treated with radium-223. We observed greater radium-223 radioactivity levels in metastatic bone tumor containing biopsies compared with adjacent normal bone. We found evidence of persistent Cellsearch CTCs and B-ALP (+) CTCs in the majority of men over time during radium-223 therapy despite serum B-ALP normalization. We identified genomic gains in osteoblast mimicry genes including gains of ALPL, osteopontin, SPARC, OB-cadherin and loss of RUNX2, and validated genomic alterations or increased expression at the DNA and RNA level in an independent cohort of 45 men with bone-metastatic CRPC and in 150 metastatic biopsies from men with mCRPC. CONCLUSIONS: Osteomimicry may contribute in part to the uptake of radium-223 within bone metastases and may thereby enhance the therapeutic benefit of this bone targeting radiotherapy.

Authors
Armstrong, AJ; Gupta, S; Healy, P; Kemeny, G; Leith, B; Zalutsky, MR; Spritzer, C; Davies, C; Rothwell, C; Ware, K; Somarelli, JA; Wood, K; Ribar, T; Giannakakou, P; Zhang, J; Gerber, D; Anand, M; Foo, W-C; Halabi, S; Gregory, SG; George, DJ
MLA Citation
Armstrong, Andrew J., et al. “Pharmacodynamic study of radium-223 in men with bone metastatic castration resistant prostate cancer..” Plos One, vol. 14, no. 5, 2019. Pubmed, doi:10.1371/journal.pone.0216934.
PMID
31136607
Source
pubmed
Published In
Plos One
Volume
14
Issue
5
Publish Date
2019
Start Page
e0216934
DOI
10.1371/journal.pone.0216934

Synthetic lethality between HER2 and transaldolase in intrinsically resistant HER2-positive breast cancers.

Intrinsic resistance to anti-HER2 therapy in breast cancer remains an obstacle in the clinic, limiting its efficacy. However, the biological basis for intrinsic resistance is poorly understood. Here we performed a CRISPR/Cas9-mediated loss-of-function genetic profiling and identified TALDO1, which encodes the rate-limiting transaldolase (TA) enzyme in the non-oxidative pentose phosphate pathway, as essential for cellular survival following pharmacological HER2 blockade. Suppression of TA increases cell susceptibility to HER2 inhibition in two intrinsically resistant breast cancer cell lines with HER2 amplification. Mechanistically, TA depletion combined with HER2 inhibition significantly reduces cellular NADPH levels, resulting in excessive ROS production and deficient lipid and nucleotide synthesis. Importantly, higher TA expression correlates with poor response to HER2 inhibition in a breast cancer patient cohort. Together, these results pinpoint TA as a novel metabolic enzyme possessing synthetic lethality with HER2 inhibition that can potentially be exploited as a biomarker or target for combination therapy.

Authors
Ding, Y; Gong, C; Huang, D; Chen, R; Sui, P; Lin, KH; Liang, G; Yuan, L; Xiang, H; Chen, J; Yin, T; Alexander, PB; Wang, Q-F; Song, E-W; Li, Q-J; Wood, KC; Wang, X-F
MLA Citation
Ding, Yi, et al. “Synthetic lethality between HER2 and transaldolase in intrinsically resistant HER2-positive breast cancers..” Nat Commun, vol. 9, no. 1, Oct. 2018. Pubmed, doi:10.1038/s41467-018-06651-x.
PMID
30323337
Source
pubmed
Published In
Nature Communications
Volume
9
Issue
1
Publish Date
2018
Start Page
4274
DOI
10.1038/s41467-018-06651-x

Systematic mapping of BCL-2 gene dependencies in cancer reveals molecular determinants of BH3 mimetic sensitivity.

While inhibitors of BCL-2 family proteins (BH3 mimetics) have shown promise as anti-cancer agents, the various dependencies or co-dependencies of diverse cancers on BCL-2 genes remain poorly understood. Here we develop a drug screening approach to define the sensitivity of cancer cells from ten tissue types to all possible combinations of selective BCL-2, BCL-XL, and MCL-1 inhibitors and discover that most cell lines depend on at least one combination for survival. We demonstrate that expression levels of BCL-2 genes predict single mimetic sensitivity, whereas EMT status predicts synergistic dependence on BCL-XL+MCL-1. Lastly, we use a CRISPR/Cas9 screen to discover that BFL-1 and BCL-w promote resistance to all tested combinations of BCL-2, BCL-XL, and MCL-1 inhibitors. Together, these results provide a roadmap for rationally targeting BCL-2 family dependencies in diverse human cancers and motivate the development of selective BFL-1 and BCL-w inhibitors to overcome intrinsic resistance to BH3 mimetics.

Authors
Soderquist, RS; Crawford, L; Liu, E; Lu, M; Agarwal, A; Anderson, GR; Lin, KH; Winter, PS; Cakir, M; Wood, KC
MLA Citation
Soderquist, Ryan S., et al. “Systematic mapping of BCL-2 gene dependencies in cancer reveals molecular determinants of BH3 mimetic sensitivity..” Nat Commun, vol. 9, no. 1, Aug. 2018. Pubmed, doi:10.1038/s41467-018-05815-z.
PMID
30158527
Source
pubmed
Published In
Nature Communications
Volume
9
Issue
1
Publish Date
2018
Start Page
3513
DOI
10.1038/s41467-018-05815-z

An acoustofluidic trap and transfer approach for organizing a high density single cell array.

We demonstrate a hybrid microfluidic system that combines fluidic trapping and acoustic switching to organize an array of single cells at high density. The fluidic trapping step is achieved by balancing the hydrodynamic resistances of three parallel channel segments forming a microfluidic trifurcation, the purpose of which was to capture single cells in a high-density array. Next, the cells were transferred into adjacent larger compartments by generating an array of streaming micro-vortices to move the cells to the desired streamlines in a massively parallel format. This approach can compartmentalize single cells with efficiencies of ≈67% in compartments that have diameters on the order of ∼100 um, which is an appropriate size for single cell proliferation studies and other single cell biochemical measurements.

Authors
Ohiri, KA; Kelly, ST; Motschman, JD; Lin, KH; Wood, KC; Yellen, BB
MLA Citation
Ohiri, Korine A., et al. “An acoustofluidic trap and transfer approach for organizing a high density single cell array..” Lab Chip, vol. 18, no. 14, July 2018, pp. 2124–33. Pubmed, doi:10.1039/c8lc00196k.
Website
https://hdl.handle.net/10161/17203
PMID
29931016
Source
pubmed
Published In
Lab Chip
Volume
18
Issue
14
Publish Date
2018
Start Page
2124
End Page
2133
DOI
10.1039/c8lc00196k

Mapping Effector-Phenotype Landscapes in KRAS-Driven Cancers.

Oncogenic KRAS can activate numerous effector pathways to drive malignant progression. However, the relationships between specific effectors and oncogenic phenotypes, and the extent to which these relationships vary across heterogeneous tumors, are incompletely understood. Recently in Cell Reports, a team of scientists described an innovative, combinatorial siRNA-based approach to functionally link KRAS effectors and phenotypes in a large panel of cancer cell lines. Central to this work was the identification of two major subtypes of KRAS-mutant cancers with distinct effector landscapes and tractable therapeutic vulnerabilities.

Authors
Winter, PS; Wood, KC
MLA Citation
Winter, Peter S., and Kris C. Wood. “Mapping Effector-Phenotype Landscapes in KRAS-Driven Cancers..” Trends Cancer, vol. 4, no. 5, May 2018, pp. 333–35. Pubmed, doi:10.1016/j.trecan.2018.02.004.
PMID
29709255
Source
pubmed
Published In
Trends Cancer
Volume
4
Issue
5
Publish Date
2018
Start Page
333
End Page
335
DOI
10.1016/j.trecan.2018.02.004

Dysregulation of mitochondrial dynamics proteins are a targetable feature of human tumors.

Altered mitochondrial dynamics can broadly impact tumor cell physiology. Using genetic and pharmacological profiling of cancer cell lines and human tumors, we here establish that perturbations to the mitochondrial dynamics network also result in specific therapeutic vulnerabilities. In particular, through distinct mechanisms, tumors with increased mitochondrial fragmentation or connectivity are hypersensitive to SMAC mimetics, a class of compounds that induce apoptosis through inhibition of IAPs and for which robust sensitivity biomarkers remain to be identified. Further, because driver oncogenes exert dominant control over mitochondrial dynamics, oncogene-targeted therapies can be used to sensitize tumors to SMAC mimetics via their effects on fission/fusion dynamics. Collectively, these data demonstrate that perturbations to the mitochondrial dynamics network induce targetable vulnerabilities across diverse human tumors and, more broadly, suggest that the altered structures, activities, and trafficking of cellular organelles may facilitate additional cancer therapeutic opportunities.

Authors
Anderson, GR; Wardell, SE; Cakir, M; Yip, C; Ahn, Y-R; Ali, M; Yllanes, AP; Chao, CA; McDonnell, DP; Wood, KC
MLA Citation
Anderson, Grace R., et al. “Dysregulation of mitochondrial dynamics proteins are a targetable feature of human tumors..” Nat Commun, vol. 9, no. 1, Apr. 2018. Pubmed, doi:10.1038/s41467-018-04033-x.
PMID
29700304
Source
pubmed
Published In
Nature Communications
Volume
9
Issue
1
Publish Date
2018
Start Page
1677
DOI
10.1038/s41467-018-04033-x

Bayesian Approximate Kernel Regression with Variable Selection.

Nonlinear kernel regression models are often used in statistics and machine learning because they are more accurate than linear models. Variable selection for kernel regression models is a challenge partly because, unlike the linear regression setting, there is no clear concept of an effect size for regression coefficients. In this paper, we propose a novel framework that provides an effect size analog for each explanatory variable in Bayesian kernel regression models when the kernel is shift-invariant - for example, the Gaussian kernel. We use function analytic properties of shift-invariant reproducing kernel Hilbert spaces (RKHS) to define a linear vector space that: (i) captures nonlinear structure, and (ii) can be projected onto the original explanatory variables. This projection onto the original explanatory variables serves as an analog of effect sizes. The specific function analytic property we use is that shift-invariant kernel functions can be approximated via random Fourier bases. Based on the random Fourier expansion, we propose a computationally efficient class of Bayesian approximate kernel regression (BAKR) models for both nonlinear regression and binary classification for which one can compute an analog of effect sizes. We illustrate the utility of BAKR by examining two important problems in statistical genetics: genomic selection (i.e. phenotypic prediction) and association mapping (i.e. inference of significant variants or loci). State-of-the-art methods for genomic selection and association mapping are based on kernel regression and linear models, respectively. BAKR is the first method that is competitive in both settings.

Authors
Crawford, L; Wood, KC; Zhou, X; Mukherjee, S
MLA Citation
Crawford, Lorin, et al. “Bayesian Approximate Kernel Regression with Variable Selection..” J Am Stat Assoc, vol. 113, no. 524, 2018, pp. 1710–21. Pubmed, doi:10.1080/01621459.2017.1361830.
PMID
30799887
Source
pubmed
Published In
Journal of the American Statistical Association
Volume
113
Issue
524
Publish Date
2018
Start Page
1710
End Page
1721
DOI
10.1080/01621459.2017.1361830

Melanoma Therapeutic Strategies that Select against Resistance by Exploiting MYC-Driven Evolutionary Convergence.

Diverse pathways drive resistance to BRAF/MEK inhibitors in BRAF-mutant melanoma, suggesting that durable control of resistance will be a challenge. By combining statistical modeling of genomic data from matched pre-treatment and post-relapse patient tumors with functional interrogation of >20 in vitro and in vivo resistance models, we discovered that major pathways of resistance converge to activate the transcription factor, c-MYC (MYC). MYC expression and pathway gene signatures were suppressed following drug treatment, and then rebounded during progression. Critically, MYC activation was necessary and sufficient for resistance, and suppression of MYC activity using genetic approaches or BET bromodomain inhibition was sufficient to resensitize cells and delay BRAFi resistance. Finally, MYC-driven, BRAFi-resistant cells are hypersensitive to the inhibition of MYC synthetic lethal partners, including SRC family and c-KIT tyrosine kinases, as well as glucose, glutamine, and serine metabolic pathways. These insights enable the design of combination therapies that select against resistance evolution.

Authors
Singleton, KR; Crawford, L; Tsui, E; Manchester, HE; Maertens, O; Liu, X; Liberti, MV; Magpusao, AN; Stein, EM; Tingley, JP; Frederick, DT; Boland, GM; Flaherty, KT; McCall, SJ; Krepler, C; Sproesser, K; Herlyn, M; Adams, DJ; Locasale, JW; Cichowski, K; Mukherjee, S; Wood, KC
MLA Citation
Singleton, Katherine R., et al. “Melanoma Therapeutic Strategies that Select against Resistance by Exploiting MYC-Driven Evolutionary Convergence..” Cell Rep, vol. 21, no. 10, Dec. 2017, pp. 2796–812. Pubmed, doi:10.1016/j.celrep.2017.11.022.
PMID
29212027
Source
pubmed
Published In
Cell Reports
Volume
21
Issue
10
Publish Date
2017
Start Page
2796
End Page
2812
DOI
10.1016/j.celrep.2017.11.022

A Landscape of Therapeutic Cooperativity in KRAS Mutant Cancers Reveals Principles for Controlling Tumor Evolution.

Combinatorial inhibition of effector and feedback pathways is a promising treatment strategy for KRAS mutant cancers. However, the particular pathways that should be targeted to optimize therapeutic responses are unclear. Using CRISPR/Cas9, we systematically mapped the pathways whose inhibition cooperates with drugs targeting the KRAS effectors MEK, ERK, and PI3K. By performing 70 screens in models of KRAS mutant colorectal, lung, ovarian, and pancreas cancers, we uncovered universal and tissue-specific sensitizing combinations involving inhibitors of cell cycle, metabolism, growth signaling, chromatin regulation, and transcription. Furthermore, these screens revealed secondary genetic modifiers of sensitivity, yielding a SRC inhibitor-based combination therapy for KRAS/PIK3CA double-mutant colorectal cancers (CRCs) with clinical potential. Surprisingly, acquired resistance to combinations of growth signaling pathway inhibitors develops rapidly following treatment, but by targeting signaling feedback or apoptotic priming, it is possible to construct three-drug combinations that greatly delay its emergence.

Authors
Anderson, GR; Winter, PS; Lin, KH; Nussbaum, DP; Cakir, M; Stein, EM; Soderquist, RS; Crawford, L; Leeds, JC; Newcomb, R; Stepp, P; Yip, C; Wardell, SE; Tingley, JP; Ali, M; Xu, M; Ryan, M; McCall, SJ; McRee, AJ; Counter, CM; Der, CJ; Wood, KC
MLA Citation
Anderson, Grace R., et al. “A Landscape of Therapeutic Cooperativity in KRAS Mutant Cancers Reveals Principles for Controlling Tumor Evolution..” Cell Rep, vol. 20, no. 4, July 2017, pp. 999–1015. Pubmed, doi:10.1016/j.celrep.2017.07.006.
PMID
28746882
Source
pubmed
Published In
Cell Reports
Volume
20
Issue
4
Publish Date
2017
Start Page
999
End Page
1015
DOI
10.1016/j.celrep.2017.07.006

Codon bias imposes a targetable limitation on KRAS-driven therapeutic resistance.

KRAS mutations drive resistance to targeted therapies, including EGFR inhibitors in colorectal cancer (CRC). Through genetic screens, we unexpectedly find that mutant HRAS, which is rarely found in CRC, is a stronger driver of resistance than mutant KRAS. This difference is ascribed to common codon bias in HRAS, which leads to much higher protein expression, and implies that the inherent poor expression of KRAS due to rare codons must be surmounted during drug resistance. In agreement, we demonstrate that primary resistance to cetuximab is dependent upon both KRAS mutational status and protein expression level, and acquired resistance is often associated with KRASQ61 mutations that function even when protein expression is low. Finally, cancer cells upregulate translation to facilitate KRASG12-driven acquired resistance, resulting in hypersensitivity to translational inhibitors. These findings demonstrate that codon bias plays a critical role in KRAS-driven resistance and provide a rationale for targeting translation to overcome resistance.

Authors
Ali, M; Kaltenbrun, E; Anderson, GR; Stephens, SJ; Arena, S; Bardelli, A; Counter, CM; Wood, KC
MLA Citation
Ali, Moiez, et al. “Codon bias imposes a targetable limitation on KRAS-driven therapeutic resistance..” Nat Commun, vol. 8, June 2017. Pubmed, doi:10.1038/ncomms15617.
PMID
28593995
Source
pubmed
Published In
Nature Communications
Volume
8
Publish Date
2017
Start Page
15617
DOI
10.1038/ncomms15617

Epstein-Barr virus ensures B cell survival by uniquely modulating apoptosis at early and late times after infection.

Latent Epstein-Barr virus (EBV) infection is causally linked to several human cancers. EBV expresses viral oncogenes that promote cell growth and inhibit the apoptotic response to uncontrolled proliferation. The EBV oncoprotein LMP1 constitutively activates NFκB and is critical for survival of EBV-immortalized B cells. However, during early infection EBV induces rapid B cell proliferation with low levels of LMP1 and little apoptosis. Therefore, we sought to define the mechanism of survival in the absence of LMP1/NFκB early after infection. We used BH3 profiling to query mitochondrial regulation of apoptosis and defined a transition from uninfected B cells (BCL-2) to early-infected (MCL-1/BCL-2) and immortalized cells (BFL-1). This dynamic change in B cell survival mechanisms is unique to virus-infected cells and relies on regulation of MCL-1 mitochondrial localization and BFL-1 transcription by the viral EBNA3A protein. This study defines a new role for EBNA3A in the suppression of apoptosis with implications for EBV lymphomagenesis.

Authors
Price, AM; Dai, J; Bazot, Q; Patel, L; Nikitin, PA; Djavadian, R; Winter, PS; Salinas, CA; Barry, AP; Wood, KC; Johannsen, EC; Letai, A; Allday, MJ; Luftig, MA
MLA Citation
Price, Alexander M., et al. “Epstein-Barr virus ensures B cell survival by uniquely modulating apoptosis at early and late times after infection..” Elife, vol. 6, Apr. 2017. Pubmed, doi:10.7554/eLife.22509.
Website
http://hdl.handle.net/10161/14611
PMID
28425914
Source
pubmed
Published In
Elife
Volume
6
Publish Date
2017
DOI
10.7554/eLife.22509

Leveraging Synthetic Lethality to Target Convergent Therapeutic Resistance

Authors
Wood, KC
MLA Citation
Wood, Kris C. “Leveraging Synthetic Lethality to Target Convergent Therapeutic Resistance.” Faseb Journal, vol. 31, FEDERATION AMER SOC EXP BIOL, 2017.
Source
wos
Published In
Faseb Journal
Volume
31
Publish Date
2017

Suppressing oncogenic transcription with a little healthy competition.

Therapeutic strategies that stabilize wild-type MLL proteins have selective activity in MLL-rearranged leukemias.

Authors
Wood, KC
MLA Citation
Wood, Kris C. “Suppressing oncogenic transcription with a little healthy competition..” Sci Transl Med, vol. 9, no. 374, Jan. 2017. Pubmed, doi:10.1126/scitranslmed.aal5000.
PMID
28123073
Source
pubmed
Published In
Sci Transl Med
Volume
9
Issue
374
Publish Date
2017
DOI
10.1126/scitranslmed.aal5000

PIK3CA mutations enable targeting of a breast tumor dependency through mTOR-mediated MCL-1 translation.

Therapies that efficiently induce apoptosis are likely to be required for durable clinical responses in patients with solid tumors. Using a pharmacological screening approach, we discovered that combined inhibition of B cell lymphoma-extra large (BCL-XL) and the mammalian target of rapamycin (mTOR)/4E-BP axis results in selective and synergistic induction of apoptosis in cellular and animal models of PIK3CA mutant breast cancers, including triple-negative tumors. Mechanistically, inhibition of mTOR/4E-BP suppresses myeloid cell leukemia-1 (MCL-1) protein translation only in PIK3CA mutant tumors, creating a synthetic dependence on BCL-XL This dual dependence on BCL-XL and MCL-1, but not on BCL-2, appears to be a fundamental property of diverse breast cancer cell lines, xenografts, and patient-derived tumors that is independent of the molecular subtype or PIK3CA mutational status. Furthermore, this dependence distinguishes breast cancers from normal breast epithelial cells, which are neither primed for apoptosis nor dependent on BCL-XL/MCL-1, suggesting a potential therapeutic window. By tilting the balance of pro- to antiapoptotic signals in the mitochondria, dual inhibition of MCL-1 and BCL-XL also sensitizes breast cancer cells to standard-of-care cytotoxic and targeted chemotherapies. Together, these results suggest that patients with PIK3CA mutant breast cancers may benefit from combined treatment with inhibitors of BCL-XL and the mTOR/4E-BP axis, whereas alternative methods of inhibiting MCL-1 and BCL-XL may be effective in tumors lacking PIK3CA mutations.

Authors
Anderson, GR; Wardell, SE; Cakir, M; Crawford, L; Leeds, JC; Nussbaum, DP; Shankar, PS; Soderquist, RS; Stein, EM; Tingley, JP; Winter, PS; Zieser-Misenheimer, EK; Alley, HM; Yllanes, A; Haney, V; Blackwell, KL; McCall, SJ; McDonnell, DP; Wood, KC
MLA Citation
Anderson, Grace R., et al. “PIK3CA mutations enable targeting of a breast tumor dependency through mTOR-mediated MCL-1 translation..” Sci Transl Med, vol. 8, no. 369, Dec. 2016. Pubmed, doi:10.1126/scitranslmed.aae0348.
Website
http://hdl.handle.net/10161/13335
PMID
27974663
Source
pubmed
Published In
Sci Transl Med
Volume
8
Issue
369
Publish Date
2016
Start Page
369ra175
DOI
10.1126/scitranslmed.aae0348

An EXITS strategy for decreasing cancer risk in women.

Authors
Wood, KC
MLA Citation
Wood, Kris C. “An EXITS strategy for decreasing cancer risk in women..” Sci Transl Med, vol. 8, no. 368, Dec. 2016. Pubmed, doi:10.1126/scitranslmed.aal2806.
PMID
27928023
Source
pubmed
Published In
Sci Transl Med
Volume
8
Issue
368
Publish Date
2016
Start Page
368ec197
DOI
10.1126/scitranslmed.aal2806

Hacking T cells with synthetic circuits to program antitumor responses

Authors
Wood, KC
MLA Citation
Wood, K. C. “Hacking T cells with synthetic circuits to program antitumor responses.” Science Translational Medicine, vol. 8, no. 362, Oct. 2016. Scopus, doi:10.1126/scitranslmed.aai9170.
Source
scopus
Published In
Science Translational Medicine
Volume
8
Issue
362
Publish Date
2016
DOI
10.1126/scitranslmed.aai9170

Two faces of circulating breast cancer cells

Authors
Wood, KC
MLA Citation
Wood, K. C. “Two faces of circulating breast cancer cells.” Science Translational Medicine, vol. 8, no. 356, Sept. 2016. Scopus, doi:10.1126/scitranslmed.aah7023.
Source
scopus
Published In
Science Translational Medicine
Volume
8
Issue
356
Publish Date
2016
DOI
10.1126/scitranslmed.aah7023

Mapping a path for precision cancer therapies

Authors
Wood, KC
MLA Citation
Wood, K. C. “Mapping a path for precision cancer therapies.” Science Translational Medicine, vol. 8, no. 348, July 2016. Scopus, doi:10.1126/scitranslmed.aah4512.
Source
scopus
Published In
Science Translational Medicine
Volume
8
Issue
348
Publish Date
2016
DOI
10.1126/scitranslmed.aah4512

Narrowing the focus: a toolkit to systematically connect oncogenic signaling pathways with cancer phenotypes.

Functional genomics approaches such as gain- and loss-of-function screening can efficiently reveal genes that control cancer cell growth, survival, signal transduction, and drug resistance, but distilling the results of large-scale screens into actionable therapeutic strategies is challenging given our incomplete understanding of the functions of many genes. Research over several decades, including the results of large-scale cancer sequencing projects, has made it clear that many oncogenic properties are controlled by a common set of core oncogenic signaling pathways. By directly screening this core set of pathways, rather than much larger numbers of individual genes, it may be possible to more directly and efficiently connect functional genomic screening results with therapeutic targets. Here, we describe the recent development of methods to directly screen oncogenic pathways in high-throughput. We summarize the results of studies that have used pathway-centric screening to map the pathways of resistance to targeted therapies in diverse cancer types, then conclude by expanding on potential future applications of this approach.

Authors
Singleton, KR; Wood, KC
MLA Citation
Singleton, Katherine R., and Kris C. Wood. “Narrowing the focus: a toolkit to systematically connect oncogenic signaling pathways with cancer phenotypes..” Genes Cancer, vol. 7, no. 7–8, July 2016, pp. 218–28. Pubmed, doi:10.18632/genesandcancer.112.
Website
http://hdl.handle.net/10161/13336
PMID
27738492
Source
pubmed
Published In
Genes and Cancer
Volume
7
Issue
7-8
Publish Date
2016
Start Page
218
End Page
228
DOI
10.18632/genesandcancer.112

Targeting the cancer cells that just won't go away

Authors
Wood, KC
MLA Citation
Wood, K. C. “Targeting the cancer cells that just won't go away.” Science Translational Medicine, vol. 8, no. 344, June 2016. Scopus, doi:10.1126/scitranslmed.aag2112.
Source
scopus
Published In
Science Translational Medicine
Volume
8
Issue
344
Publish Date
2016
DOI
10.1126/scitranslmed.aag2112

Targeting MCL-1/BCL-XL Forestalls the Acquisition of Resistance to ABT-199 in Acute Myeloid Leukemia.

ABT-199, a potent and selective small-molecule antagonist of BCL-2, is being clinically vetted as pharmacotherapy for the treatment of acute myeloid leukemia (AML). However, given that prolonged monotherapy tends to beget resistance, we sought to investigate the means by which resistance to ABT-199 might arise in AML and the extent to which those mechanisms might be preempted. Here we used a pathway-activating genetic screen to nominate MCL-1 and BCL-XL as potential nodes of resistance. We then characterized a panel of ABT-199-resistant myeloid leukemia cell lines derived through chronic exposure to ABT-199 and found that acquired drug resistance is indeed driven by the upregulation of MCL-1 and BCL-XL. By targeting MCL-1 and BCL-XL, resistant AML cell lines could be resensitized to ABT-199. Further, preemptively targeting MCL-1 and/or BCL-XL alongside administration of ABT-199 was capable of delaying or forestalling the acquisition of drug resistance. Collectively, these data suggest that in AML, (1) the selection of initial therapy dynamically templates the landscape of acquired resistance via modulation of MCL-1/BCL-XL and (2) appropriate selection of initial therapy may delay or altogether forestall the acquisition of resistance to ABT-199.

Authors
Lin, KH; Winter, PS; Xie, A; Roth, C; Martz, CA; Stein, EM; Anderson, GR; Tingley, JP; Wood, KC
MLA Citation
Lin, Kevin H., et al. “Targeting MCL-1/BCL-XL Forestalls the Acquisition of Resistance to ABT-199 in Acute Myeloid Leukemia..” Sci Rep, vol. 6, June 2016. Pubmed, doi:10.1038/srep27696.
PMID
27283158
Source
pubmed
Published In
Scientific Reports
Volume
6
Publish Date
2016
Start Page
27696
DOI
10.1038/srep27696

An Automated High-throughput Array Microscope for Cancer Cell Mechanics.

Changes in cellular mechanical properties correlate with the progression of metastatic cancer along the epithelial-to-mesenchymal transition (EMT). Few high-throughput methodologies exist that measure cell compliance, which can be used to understand the impact of genetic alterations or to screen the efficacy of chemotherapeutic agents. We have developed a novel array high-throughput microscope (AHTM) system that combines the convenience of the standard 96-well plate with the ability to image cultured cells and membrane-bound microbeads in twelve independently-focusing channels simultaneously, visiting all wells in eight steps. We use the AHTM and passive bead rheology techniques to determine the relative compliance of human pancreatic ductal epithelial (HPDE) cells, h-TERT transformed HPDE cells (HPNE), and four gain-of-function constructs related to EMT. The AHTM found HPNE, H-ras, Myr-AKT, and Bcl2 transfected cells more compliant relative to controls, consistent with parallel tests using atomic force microscopy and invasion assays, proving the AHTM capable of screening for changes in mechanical phenotype.

Authors
Cribb, JA; Osborne, LD; Beicker, K; Psioda, M; Chen, J; O'Brien, ET; Taylor Ii, RM; Vicci, L; Hsiao, JP-L; Shao, C; Falvo, M; Ibrahim, JG; Wood, KC; Blobe, GC; Superfine, R
MLA Citation
Cribb, Jeremy A., et al. “An Automated High-throughput Array Microscope for Cancer Cell Mechanics..” Sci Rep, vol. 6, June 2016. Pubmed, doi:10.1038/srep27371.
PMID
27265611
Source
pubmed
Published In
Scientific Reports
Volume
6
Publish Date
2016
Start Page
27371
DOI
10.1038/srep27371

Collaborating tumor cells overcome multitargeted antiangiogenic therapies

Authors
Wood, KC
MLA Citation
Wood, K. C. “Collaborating tumor cells overcome multitargeted antiangiogenic therapies.” Science Translational Medicine, vol. 8, no. 338, May 2016. Scopus, doi:10.1126/scitranslmed.aaf9190.
Source
scopus
Published In
Science Translational Medicine
Volume
8
Issue
338
Publish Date
2016
DOI
10.1126/scitranslmed.aaf9190

ERRα-Regulated Lactate Metabolism Contributes to Resistance to Targeted Therapies in Breast Cancer.

Imaging studies in animals and in humans have indicated that the oxygenation and nutritional status of solid tumors is dynamic. Furthermore, the extremely low level of glucose within tumors, while reflecting its rapid uptake and metabolism, also suggests that cancer cells must rely on other energy sources in some circumstances. Here, we find that some breast cancer cells can switch to utilizing lactate as a primary source of energy, allowing them to survive glucose deprivation for extended periods, and that this activity confers resistance to PI3K/mTOR inhibitors. The nuclear receptor, estrogen-related receptor alpha (ERRα), was shown to regulate the expression of genes required for lactate utilization, and isotopomer analysis revealed that genetic or pharmacological inhibition of ERRα activity compromised lactate oxidation. Importantly, ERRα antagonists increased the in vitro and in vivo efficacy of PI3K/mTOR inhibitors, highlighting the potential clinical utility of this drug combination.

Authors
Park, S; Chang, C-Y; Safi, R; Liu, X; Baldi, R; Jasper, JS; Anderson, GR; Liu, T; Rathmell, JC; Dewhirst, MW; Wood, KC; Locasale, JW; McDonnell, DP
MLA Citation
Park, Sunghee, et al. “ERRα-Regulated Lactate Metabolism Contributes to Resistance to Targeted Therapies in Breast Cancer..” Cell Rep, vol. 15, no. 2, Apr. 2016, pp. 323–35. Pubmed, doi:10.1016/j.celrep.2016.03.026.
PMID
27050525
Source
pubmed
Published In
Cell Reports
Volume
15
Issue
2
Publish Date
2016
Start Page
323
End Page
335
DOI
10.1016/j.celrep.2016.03.026

Intercepting reversible drug tolerance to improve targeted therapy

Authors
Wood, KC
MLA Citation
Wood, K. C. “Intercepting reversible drug tolerance to improve targeted therapy.” Science Translational Medicine, vol. 8, no. 332, Mar. 2016. Scopus, doi:10.1126/scitranslmed.aaf6467.
Source
scopus
Published In
Science Translational Medicine
Volume
8
Issue
332
Publish Date
2016
DOI
10.1126/scitranslmed.aaf6467

Cooperative nutrient accumulation sustains growth of mammalian cells.

The coordination of metabolic processes to allow increased nutrient uptake and utilization for macromolecular synthesis is central for cell growth. Although studies of bulk cell populations have revealed important metabolic and signaling requirements that impact cell growth on long time scales, whether the same regulation influences short-term cell growth remains an open question. Here we investigate cell growth by monitoring mass accumulation of mammalian cells while rapidly depleting particular nutrients. Within minutes following the depletion of glucose or glutamine, we observe a growth reduction that is larger than the mass accumulation rate of the nutrient. This indicates that if one particular nutrient is depleted, the cell rapidly adjusts the amount that other nutrients are accumulated, which is consistent with cooperative nutrient accumulation. Population measurements of nutrient sensing pathways involving mTOR, AKT, ERK, PKA, MST1, or AMPK, or pro-survival pathways involving autophagy suggest that they do not mediate this growth reduction. Furthermore, the protein synthesis rate does not change proportionally to the mass accumulation rate over these time scales, suggesting that intracellular metabolic pools buffer the growth response. Our findings demonstrate that cell growth can be regulated over much shorter time scales than previously appreciated.

Authors
Son, S; Stevens, MM; Chao, HX; Thoreen, C; Hosios, AM; Schweitzer, LD; Weng, Y; Wood, K; Sabatini, D; Vander Heiden, MG; Manalis, S
MLA Citation
Son, Sungmin, et al. “Cooperative nutrient accumulation sustains growth of mammalian cells..” Sci Rep, vol. 5, Dec. 2015. Pubmed, doi:10.1038/srep17401.
PMID
26620632
Source
pubmed
Published In
Scientific Reports
Volume
5
Publish Date
2015
Start Page
17401
DOI
10.1038/srep17401

Mapping the Pathways of Resistance to Targeted Therapies.

Resistance substantially limits the depth and duration of clinical responses to targeted anticancer therapies. Through the use of complementary experimental approaches, investigators have revealed that cancer cells can achieve resistance through adaptation or selection driven by specific genetic, epigenetic, or microenvironmental alterations. Ultimately, these diverse alterations often lead to the activation of signaling pathways that, when co-opted, enable cancer cells to survive drug treatments. Recently developed methods enable the direct and scalable identification of the signaling pathways capable of driving resistance in specific contexts. Using these methods, novel pathways of resistance to clinically approved drugs have been identified and validated. By combining systematic resistance pathway mapping methods with studies revealing biomarkers of specific resistance pathways and pharmacologic approaches to block these pathways, it may be possible to rationally construct drug combinations that yield more penetrant and lasting responses in patients.

Authors
Wood, KC
MLA Citation
Wood, Kris C. “Mapping the Pathways of Resistance to Targeted Therapies..” Cancer Res, vol. 75, no. 20, Oct. 2015, pp. 4247–51. Pubmed, doi:10.1158/0008-5472.CAN-15-1248.
PMID
26392071
Source
pubmed
Published In
Cancer Res
Volume
75
Issue
20
Publish Date
2015
Start Page
4247
End Page
4251
DOI
10.1158/0008-5472.CAN-15-1248

Vertical suppression of the EGFR pathway prevents onset of resistance in colorectal cancers.

Molecular targeted drugs are clinically effective anti-cancer therapies. However, tumours treated with single agents usually develop resistance. Here we use colorectal cancer (CRC) as a model to study how the acquisition of resistance to EGFR-targeted therapies can be restrained. Pathway-oriented genetic screens reveal that CRC cells escape from EGFR blockade by downstream activation of RAS-MEK signalling. Following treatment of CRC cells with anti-EGFR, anti-MEK or the combination of the two drugs, we find that EGFR blockade alone triggers acquired resistance in weeks, while combinatorial treatment does not induce resistance. In patient-derived xenografts, EGFR-MEK combination prevents the development of resistance. We employ mathematical modelling to provide a quantitative understanding of the dynamics of response and resistance to these single and combination therapies. Mechanistically, we find that the EGFR-MEK Combo blockade triggers Bcl-2 and Mcl-1 downregulation and initiates apoptosis. These results provide the rationale for clinical trials aimed at preventing rather than intercepting resistance.

Authors
Misale, S; Bozic, I; Tong, J; Peraza-Penton, A; Lallo, A; Baldi, F; Lin, KH; Truini, M; Trusolino, L; Bertotti, A; Di Nicolantonio, F; Nowak, MA; Zhang, L; Wood, KC; Bardelli, A
MLA Citation
Misale, Sandra, et al. “Vertical suppression of the EGFR pathway prevents onset of resistance in colorectal cancers..” Nat Commun, vol. 6, Sept. 2015. Pubmed, doi:10.1038/ncomms9305.
PMID
26392303
Source
pubmed
Published In
Nature Communications
Volume
6
Publish Date
2015
Start Page
8305
DOI
10.1038/ncomms9305

Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation.

Activation of CD4+ T cells results in rapid proliferation and differentiation into effector and regulatory subsets. CD4+ effector T cell (Teff) (Th1 and Th17) and Treg subsets are metabolically distinct, yet the specific metabolic differences that modify T cell populations are uncertain. Here, we evaluated CD4+ T cell populations in murine models and determined that inflammatory Teffs maintain high expression of glycolytic genes and rely on high glycolytic rates, while Tregs are oxidative and require mitochondrial electron transport to proliferate, differentiate, and survive. Metabolic profiling revealed that pyruvate dehydrogenase (PDH) is a key bifurcation point between T cell glycolytic and oxidative metabolism. PDH function is inhibited by PDH kinases (PDHKs). PDHK1 was expressed in Th17 cells, but not Th1 cells, and at low levels in Tregs, and inhibition or knockdown of PDHK1 selectively suppressed Th17 cells and increased Tregs. This alteration in the CD4+ T cell populations was mediated in part through ROS, as N-acetyl cysteine (NAC) treatment restored Th17 cell generation. Moreover, inhibition of PDHK1 modulated immunity and protected animals against experimental autoimmune encephalomyelitis, decreasing Th17 cells and increasing Tregs. Together, these data show that CD4+ subsets utilize and require distinct metabolic programs that can be targeted to control specific T cell populations in autoimmune and inflammatory diseases.

Authors
Gerriets, VA; Kishton, RJ; Nichols, AG; Macintyre, AN; Inoue, M; Ilkayeva, O; Winter, PS; Liu, X; Priyadharshini, B; Slawinska, ME; Haeberli, L; Huck, C; Turka, LA; Wood, KC; Hale, LP; Smith, PA; Schneider, MA; MacIver, NJ; Locasale, JW; Newgard, CB; Shinohara, ML; Rathmell, JC
MLA Citation
Gerriets, Valerie A., et al. “Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation..” J Clin Invest, vol. 125, no. 1, Jan. 2015, pp. 194–207. Pubmed, doi:10.1172/JCI76012.
Website
http://hdl.handle.net/10161/10313
PMID
25437876
Source
pubmed
Published In
J Clin Invest
Volume
125
Issue
1
Publish Date
2015
Start Page
194
End Page
207
DOI
10.1172/JCI76012

Systematic identification of signaling pathways with potential to confer anticancer drug resistance.

Cancer cells can activate diverse signaling pathways to evade the cytotoxic action of drugs. We created and screened a library of barcoded pathway-activating mutant complementary DNAs to identify those that enhanced the survival of cancer cells in the presence of 13 clinically relevant, targeted therapies. We found that activation of the RAS-MAPK (mitogen-activated protein kinase), Notch1, PI3K (phosphoinositide 3-kinase)-mTOR (mechanistic target of rapamycin), and ER (estrogen receptor) signaling pathways often conferred resistance to this selection of drugs. Activation of the Notch1 pathway promoted acquired resistance to tamoxifen (an ER-targeted therapy) in serially passaged breast cancer xenografts in mice, and treating mice with a γ-secretase inhibitor to inhibit Notch signaling restored tamoxifen sensitivity. Markers of Notch1 activity in tumor tissue correlated with resistance to tamoxifen in breast cancer patients. Similarly, activation of Notch1 signaling promoted acquired resistance to MAPK inhibitors in BRAF(V600E) melanoma cells in culture, and the abundance of Notch1 pathway markers was increased in tumors from a subset of melanoma patients. Thus, Notch1 signaling may be a therapeutic target in some drug-resistant breast cancers and melanomas. Additionally, multiple resistance pathways were activated in melanoma cell lines with intrinsic resistance to MAPK inhibitors, and simultaneous inhibition of these pathways synergistically induced drug sensitivity. These data illustrate the potential for systematic identification of the signaling pathways controlling drug resistance that could inform clinical strategies and drug development for multiple types of cancer. This approach may also be used to advance clinical options in other disease contexts.

Authors
Martz, CA; Ottina, KA; Singleton, KR; Jasper, JS; Wardell, SE; Peraza-Penton, A; Anderson, GR; Winter, PS; Wang, T; Alley, HM; Kwong, LN; Cooper, ZA; Tetzlaff, M; Chen, P-L; Rathmell, JC; Flaherty, KT; Wargo, JA; McDonnell, DP; Sabatini, DM; Wood, KC
MLA Citation
Martz, Colin A., et al. “Systematic identification of signaling pathways with potential to confer anticancer drug resistance..” Sci Signal, vol. 7, no. 357, Dec. 2014. Pubmed, doi:10.1126/scisignal.aaa1877.
PMID
25538079
Source
pubmed
Published In
Sci Signal
Volume
7
Issue
357
Publish Date
2014
Start Page
ra121
DOI
10.1126/scisignal.aaa1877

RAS signaling promotes resistance to JAK inhibitors by suppressing BAD-mediated apoptosis.

Myeloproliferative neoplasms (MPNs) frequently have an activating mutation in the gene encoding Janus kinase 2 (JAK2). Thus, targeting the pathway mediated by JAK and its downstream substrate, signal transducer and activator of transcription (STAT), may yield clinical benefit for patients with MPNs containing the JAK2(V617F) mutation. Although JAK inhibitor therapy reduces splenomegaly and improves systemic symptoms in patients, this treatment does not appreciably reduce the number of neoplastic cells. To identify potential mechanisms underlying this inherent resistance phenomenon, we performed pathway-centric, gain-of-function screens in JAK2(V617F) hematopoietic cells and found that the activation of the guanosine triphosphatase (GTPase) RAS or its effector pathways [mediated by the kinases AKT and ERK (extracellular signal-regulated kinase)] renders cells insensitive to JAK inhibition. Resistant MPN cells became sensitized to JAK inhibitors when also exposed to inhibitors of the AKT or ERK pathways. Mechanistically, in JAK2(V617F) cells, a JAK2-mediated inactivating phosphorylation of the proapoptotic protein BAD [B cell lymphoma 2 (BCL-2)-associated death promoter] promoted cell survival. In sensitive cells, exposure to a JAK inhibitor resulted in dephosphorylation of BAD, enabling BAD to bind and sequester the prosurvival protein BCL-XL (BCL-2-like 1), thereby triggering apoptosis. In resistant cells, RAS effector pathways maintained BAD phosphorylation in the presence of JAK inhibitors, yielding a specific dependence on BCL-XL for survival. In patients with MPNs, activating mutations in RAS co-occur with the JAK2(V617F) mutation in the malignant cells, suggesting that RAS effector pathways likely play an important role in clinically observed resistance.

Authors
Winter, PS; Sarosiek, KA; Lin, KH; Meggendorfer, M; Schnittger, S; Letai, A; Wood, KC
MLA Citation
Winter, Peter S., et al. “RAS signaling promotes resistance to JAK inhibitors by suppressing BAD-mediated apoptosis..” Sci Signal, vol. 7, no. 357, Dec. 2014. Pubmed, doi:10.1126/scisignal.2005301.
PMID
25538080
Source
pubmed
Published In
Sci Signal
Volume
7
Issue
357
Publish Date
2014
Start Page
ra122
DOI
10.1126/scisignal.2005301

Uncovering scaling laws to infer multidrug response of resistant microbes and cancer cells.

Drug resistance in bacterial infections and cancers constitutes a major threat to human health. Treatments often include several interacting drugs, but even potent therapies can become ineffective in resistant mutants. Here, we simplify the picture of drug resistance by identifying scaling laws that unify the multidrug responses of drug-sensitive and -resistant cells. On the basis of these scaling relationships, we are able to infer the two-drug response of resistant mutants in previously unsampled regions of dosage space in clinically relevant microbes such as E. coli, E. faecalis, S. aureus, and S. cerevisiae as well as human non-small-cell lung cancer, melanoma, and breast cancer stem cells. Importantly, we find that scaling relations also apply across evolutionarily close strains. Finally, scaling allows one to rapidly identify new drug combinations and predict potent dosage regimes for targeting resistant mutants without any prior mechanistic knowledge about the specific resistance mechanism.

Authors
Wood, KB; Wood, KC; Nishida, S; Cluzel, P
MLA Citation
Wood, Kevin B., et al. “Uncovering scaling laws to infer multidrug response of resistant microbes and cancer cells..” Cell Rep, vol. 6, no. 6, Mar. 2014, pp. 1073–84. Pubmed, doi:10.1016/j.celrep.2014.02.007.
PMID
24613352
Source
pubmed
Published In
Cell Reports
Volume
6
Issue
6
Publish Date
2014
Start Page
1073
End Page
1084
DOI
10.1016/j.celrep.2014.02.007

Science signaling podcast: 23 December 2014

This Podcast features an interview with Kris Wood, senior author of two Research Articles that appear in the 23 December 2014 issue of Science Signaling, about signaling pathways that enable cancer cells to develop drug resistance. Myeloprolfierative neoplasms, which are overgrowths of bone marrow cells that may progress to leukemia, are often resistant to Janus kinase (JAK) inhibitors despite having activating mutations in JAK2. Winter et al. found that increased RAS signaling in a subset of these cells led to inactivation of the proapoptotic protein BAD and that simultaneously inhibiting JAK and RAS signaling overcame resistance. In a related study, Martz et al. performed a screen to identify signaling pathways that, when activated, conferred resistance to several clinically relevant, targeted cancer therapies. The authors identified Notch1 signaling as important for enabling several different types of cancer cells to develop resistance to various anticancer drugs. These findings suggest combination therapies that could be attempted in the clinic using existing drugs.

Authors
Wood, KC; VanHook, AM
MLA Citation
Wood, K. C., and A. M. VanHook. “Science signaling podcast: 23 December 2014.” Science Signaling, vol. 7, no. 357, Jan. 2014. Scopus, doi:10.1126/scisignal.aaa4213.
Source
scopus
Published In
Science Signaling
Volume
7
Issue
357
Publish Date
2014
DOI
10.1126/scisignal.aaa4213

MicroSCALE screening reveals genetic modifiers of therapeutic response in melanoma.

Cell microarrays are a promising tool for performing large-scale functional genomic screening in mammalian cells at reasonable cost, but owing to technical limitations they have been restricted for use with a narrow range of cell lines and short-term assays. Here, we describe MicroSCALE (Microarrays of Spatially Confined Adhesive Lentiviral Features), a cell microarray-based platform that enables application of this technology to a wide range of cell types and longer-term assays. We used MicroSCALE to uncover kinases that when overexpressed partially desensitized B-RAFV600E-mutant melanoma cells to inhibitors of the mitogen-activated protein kinase kinase kinase (MAPKKK) RAF, the MAPKKs MEK1 and 2 (MEK1/2, mitogen-activated protein kinase kinase 1 and 2), mTOR (mammalian target of rapamycin), or PI3K (phosphatidylinositol 3-kinase). These screens indicated that cells treated with inhibitors acting through common mechanisms were affected by a similar profile of overexpressed proteins. In contrast, screens involving inhibitors acting through distinct mechanisms yielded unique profiles, a finding that has potential relevance for small-molecule target identification and combination drugging studies. Further, by integrating large-scale functional screening results with cancer cell line gene expression and pharmacological sensitivity data, we validated the nuclear factor κB pathway as a potential mediator of resistance to MAPK pathway inhibitors. The MicroSCALE platform described here may enable new classes of large-scale, resource-efficient screens that were not previously feasible, including those involving combinations of cell lines, perturbations, and assay outputs or those involving limited numbers of cells and limited or expensive reagents.

Authors
Wood, KC; Konieczkowski, DJ; Johannessen, CM; Boehm, JS; Tamayo, P; Botvinnik, OB; Mesirov, JP; Hahn, WC; Root, DE; Garraway, LA; Sabatini, DM
MLA Citation
Wood, Kris C., et al. “MicroSCALE screening reveals genetic modifiers of therapeutic response in melanoma..” Sci Signal, vol. 5, no. 224, May 2012. Pubmed, doi:10.1126/scisignal.2002612.
PMID
22589389
Source
pubmed
Published In
Sci Signal
Volume
5
Issue
224
Publish Date
2012
Start Page
rs4
DOI
10.1126/scisignal.2002612

Growth signaling at the nexus of stem cell life and death.

Stress can activate tumor-suppressive mechanisms, causing the loss of adult stem cell function with age. In this issue of Cell Stem Cell and in Nature, Castilho et al. (2009) and Harrison et al. (2009) highlight the importance of mTOR signaling in stem cell exhaustion and mammalian aging, respectively.

Authors
Wood, KC; Sabatini, DM
MLA Citation
Wood, Kris C., and David M. Sabatini. “Growth signaling at the nexus of stem cell life and death..” Cell Stem Cell, vol. 5, no. 3, Sept. 2009, pp. 232–34. Pubmed, doi:10.1016/j.stem.2009.08.008.
PMID
19733530
Source
pubmed
Published In
Cell Stem Cell
Volume
5
Issue
3
Publish Date
2009
Start Page
232
End Page
234
DOI
10.1016/j.stem.2009.08.008

Electroactive controlled release thin films.

We present the fabrication of nanoscale electroactive thin films that can be engineered to undergo remotely controlled dissolution in the presence of a small applied voltage (+1.25 V) to release precise quantities of chemical agents. These films, which are assembled by using a nontoxic, FDA-approved, electroactive material known as Prussian Blue, are stable enough to release a fraction of their contents after the application of a voltage and then to restabilize upon its removal. As a result, it is possible to externally trigger agent release, exert control over the relative quantity of agents released from a film, and release multiple doses from one or more films in a single solution. These electroactive systems may be rapidly and conformally coated onto a wide range of substrates without regard to size, shape, or chemical composition, and as such they may find use in a host of new applications in drug delivery as well as the related fields of tissue engineering, medical diagnostics, and chemical detection.

Authors
Wood, KC; Zacharia, NS; Schmidt, DJ; Wrightman, SN; Andaya, BJ; Hammond, PT
MLA Citation
Wood, Kris C., et al. “Electroactive controlled release thin films..” Proc Natl Acad Sci U S A, vol. 105, no. 7, Feb. 2008, pp. 2280–85. Pubmed, doi:10.1073/pnas.0706994105.
PMID
18272499
Source
pubmed
Published In
Proc Natl Acad Sci U S A
Volume
105
Issue
7
Publish Date
2008
Start Page
2280
End Page
2285
DOI
10.1073/pnas.0706994105

Tumor-targeted gene delivery using molecularly engineered hybrid polymers functionalized with a tumor-homing peptide.

Before gene therapy can be used in clinical settings, safe and efficient DNA delivery systems must be developed to overcome a range of extra- and intracellular transport barriers. As a step toward the development of a modular, multifunctional gene delivery system to overcome these diverse barriers, we have developed a family of linear-dendritic "hybrid" polymers which contain functionalities for tissue targeting, minimization of nonspecific interactions, endosomal buffering, and DNA binding. Here, we demonstrate the rapid three-step, room-temperature, aqueous synthesis of hybrid polymers, as well as the functionalization of these polymers with a peptide targeting ligand that specifically binds to glucose-regulated protein-78 kDa (GRP-78), a clinically relevant tumor antigen identified in human cancer patients. These polymer systems can condense plasmid DNA into small nanoparticle structures (<210 nm) and transfect cells expressing GRP-78 with efficiencies that exceed that of branched polyethylenimine (bPEI), one of the best commercially available polymers for in vitro transfections. The synthetic approach described here may be useful for the rapid synthesis and optimization of polymer gene delivery systems bearing a range of diverse functional domains, and the specific GRP-78-targeted systems developed in this study may potentially have clinical applications in cancer gene therapy.

Authors
Wood, KC; Azarin, SM; Arap, W; Pasqualini, R; Langer, R; Hammond, PT
MLA Citation
Wood, Kris C., et al. “Tumor-targeted gene delivery using molecularly engineered hybrid polymers functionalized with a tumor-homing peptide..” Bioconjug Chem, vol. 19, no. 2, Feb. 2008, pp. 403–05. Pubmed, doi:10.1021/bc700408r.
PMID
18189340
Source
pubmed
Published In
Bioconjugate Chemistry
Volume
19
Issue
2
Publish Date
2008
Start Page
403
End Page
405
DOI
10.1021/bc700408r

Controlling interlayer diffusion to achieve sustained, multiagent delivery from layer-by-layer thin films

We present the fabrication of conformal, hydrolytically degradable thin films capable of administering sustained, multiagent release profiles. Films are constructed one molecular layer at a time by using the layer-by-layer, directed-deposition technique; the subsequent hydrolytic surface erosion of these systems results in the release of incorporated materials in a sequence that reflects their relative positions in the film. The position of each species is determined by its ability to diffuse throughout the film architecture, and, as such, the major focus of this work is to define strategies that physically block interlayer diffusion during assembly to create multicomponent, stratified films. By using a series of radiolabeled polyelectrolytes as experimental probes, we show that covalently crosslinked barriers can effectively block interlayer diffusion, leading to compartmentalized structures, although even very large numbers of ionically crosslinked (degradable or nondegradable) barrier layers cannot block interlayer diffusion. By using these principles, we designed degradable films capable of extended release as well as both parallel and serial multiagent release. The ability to fabricate multicomponent thin films with nanoscale resolution may lead to a host of new materials and applications. © 2006 by The National Academy of Sciences of the USA.

Authors
Wood, KC; Chuang, HF; Batten, RD; Lynn, DM; Hammond, PT
MLA Citation
Wood, K. C., et al. “Controlling interlayer diffusion to achieve sustained, multiagent delivery from layer-by-layer thin films.” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 27, July 2006, pp. 10207–12. Scopus, doi:10.1073/pnas.0602884103.
Source
scopus
Published In
Proceedings of the National Academy of Sciences of the United States of America
Volume
103
Issue
27
Publish Date
2006
Start Page
10207
End Page
10212
DOI
10.1073/pnas.0602884103

A family of hierarchically self-assembling linear-dendritic hybrid polymers for highly efficient targeted gene delivery.

Authors
Wood, KC; Little, SR; Langer, R; Hammond, PT
MLA Citation
Wood, Kris C., et al. “A family of hierarchically self-assembling linear-dendritic hybrid polymers for highly efficient targeted gene delivery..” Angew Chem Int Ed Engl, vol. 44, no. 41, Oct. 2005, pp. 6704–08. Pubmed, doi:10.1002/anie.200502152.
PMID
16173106
Source
pubmed
Published In
Angewandte Chemie International Edition
Volume
44
Issue
41
Publish Date
2005
Start Page
6704
End Page
6708
DOI
10.1002/anie.200502152

Tunable drug release from hydrolytically degradable layer-by-layer thin films

The development of new thin film fabrication techniques that allow for precise control of degradation and drug release properties could represent an important advance in the fields of drug delivery and biomedicine. Polyelectrolyte layer-by-layer (LBL) thin films can be assembled with nanometer scale control over spatial architecture and morphology, yet very little work has focused on the deconstruction of these ordered thin films for controlled release applications. In this study, hydrolytically degradable LBL thin films are constructed by alternately depositing a degradable poly(β-amino ester) (polymer 1) and a series of model therapeutic polysaccharides (heparin, low molecular weight heparin, and chondroitin sulfate). These films exhibit pH-dependent, pseudo-first-order degradation and release behavior. The highly versatile and tunable properties of these materials make them exciting candidates for the controlled release of a wide spectrum of therapeutics.

Authors
Wood, KC; Boedicker, JQ; Lynn, DM; Hammond, PT
MLA Citation
Wood, K. C., et al. “Tunable drug release from hydrolytically degradable layer-by-layer thin films.” Langmuir, vol. 21, no. 4, Feb. 2005, pp. 1603–09. Scopus, doi:10.1021/la0476480.
Source
scopus
Published In
Langmuir : the Acs Journal of Surfaces and Colloids
Volume
21
Issue
4
Publish Date
2005
Start Page
1603
End Page
1609
DOI
10.1021/la0476480

Degradation of chlorinated organics by membrane-immobilized nanosized metals

The use of electronegative metals, such as Fe, has been extensively studied for the treatment of ground-water containing toxic chlorinated organics. Much of the recent work has been focused on the use of nanoscale particles with diameters from 2 to 100 nm. This work examines the use of bimetallic (Fe/Ni) nanoscale particles immobilized in a cellulose acetate domain for the destruction of trichloroethylene (TCE). The organic/inorganic hybrid film is synthesized using phase inversion with sodium borohydride reduction. The resulting nanoparticles have an average diameter of 24 nm. Using a small quantity of membrane-immobilized metal (31 mg total, Fe-Ni = 4:1), it was possible to achieve over a 75% reduction in TCE levels in 4.25 h, with ethane as the only observable product. For shorter reaction times (<2 h), traces of cis- and trans-DCE could be extracted from the baseline of the MS chromatogram. For longer reaction times, products of coupling reactions (butane and hexane) were observed. This corresponds to a surface-area-normalized pseudo-first-order rate constant, k SA, for the immobilized system of 3.7 × 10 -2 L m -2 h -1. Analysis of the aqueous phase for metal content showed minimal leaching of the metals into the surrounding solution during treatment. Because various combinations of membranes containing immobilized metal nanoparticles can be achieved using the synthesis techniques presented, a more versatile platform for the application of zero-valent treatment is possible. © 2004 American Institute of Chemical Engineers Environ Prog.

Authors
Meyer, DE; Wood, K; Bachas, LG; Bhattacharyya, D
MLA Citation
Meyer, D. E., et al. “Degradation of chlorinated organics by membrane-immobilized nanosized metals.” Environmental Progress, vol. 23, no. 3, Oct. 2004, pp. 232–42. Scopus, doi:10.1002/ep.10031.
Source
scopus
Published In
Environmental Progress
Volume
23
Issue
3
Publish Date
2004
Start Page
232
End Page
242
DOI
10.1002/ep.10031
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