Senior Director and Staff Scientist, Discovery Oncology
"I find this to be an extremely exciting time in the history of oncology research."
years at Genentech
awards & honors
I joined Genentech in 2010, after having spent the previous 18 years on the faculty of Harvard Medical School. The move to Genentech was largely prompted by my steadily growing interest in the pursuit of novel therapeutic opportunities in cancer based on the rapidly accumulating understanding of molecular mechanisms underlying oncogenic processes and the response to drug treatment. I have found the research environment at Genentech to be remarkable in many respects. There is a very high bar for quality research, and decisions are always driven by the science. It’s been inspiring and exciting to work closely with such talented colleagues on such an important problem.
Being a post-doc mentor is very rewarding at several levels. It gives me the opportunity to “re-experience” the excitement of discovery that I enjoyed tremendously as a “bench scientist” many years ago when I was still performing experiments with my own hands. It’s also very satisfying to watch the development of young scientists as they mature in their approach to experimental design and data interpretation. My most important roles as a post-doc mentor are to maintain a stimulating lab environment, and to remind post-docs to pursue the most important questions and to continuously ask themselves whether they are taking the best approach to answering those questions.
Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors.
Nature. 2012 Jul 26;487(7408):505-9.
Wilson TR, Fridlyand J, Yan Y, Penuel E, Burton L, Chan E, Peng J, Lin E, Wang Y, Sosman J, Ribas A, Li J, Moffat J, Sutherlin DP, Koeppen H, Merchant M, Neve R, Settleman J.
Several recent “rationally-targeted” anti-cancer drugs have defined a paradigm shift in cancer therapy. However, progression during therapy is inevitable due to the acquisition of drug resistance. For many drugs, specific genetic mechanisms of resistance have been elucidated, and pre-clinical findings implicate additional non-genetic mechanisms. Moreover, accumulating evidence implicates heterogeneity within cancer cell populations in the response to drug treatment, posing an additional challenge to the development of cancer therapeutics.
While modeling the acute response to various anti-cancer agents in drug-sensitive tumor cell lines, we consistently observe a small subpopulation of reversibly “drug-tolerant” cells. This drug-tolerant phenotype, associated with a distinct chromatin state, is transiently acquired and relinquished at low frequency by individual cells within the population, implicating the dynamic regulation of phenotypic heterogeneity in drug tolerance. These findings suggest that cancer cell populations may employ an epigenetically-regulated dynamic survival strategy in which individual cells transiently assume a reversibly drug-tolerant state to protect the population from eradication by potentially lethal exposures.
Cancer cells typically express multiple receptor tyrosine kinases (RTKs) that mediate signals that converge on common critical downstream cell survival effectors - most notably, phosphatidylinositol 3-kinase and mitogen-activated protein kinase. Consequently, increased RTK ligand levels, via autocrine tumor cell production, paracrine contribution by tumor stroma, or systemic production, could confer resistance to inhibitors of an oncogenic kinase with a similar signaling output. Using a panel of kinase-“addicted” cancer cell lines, we found that most cells can be “rescued” from drug sensitivity by simply exposing them to one or more RTK ligands. These observations highlight the extensive redundancy of RTK-transduced signalling in cancer cells and the potentially broad role of widely expressed RTK ligands in innate and acquired resistance to drugs targeting oncogenic kinases.
Metabolic and transcriptional profiling reveals pyruvate dehydrogenase kinase 4 as a mediator of epithelial-mesenchymal transition and drug resistance in tumor cellsCancer & metabolism, 2014, ISSN: 2049-3002 View on PubMed
Overcoming EMT-associated resistance to anti-cancer drugs via Src/FAK pathway inhibitionOncotarget, 2014, ISSN: 1949-2553
AXL inhibition sensitizes mesenchymal cancer cells to anti-mitotic drugsCancer research, 2014, ISSN: 0008-5472 View on PubMed
Drug Resistance via Feedback Activation of Stat3 in Oncogene-Addicted Cancer CellsCancer Cell, 2014, ISSN: 1535-6108 View on PubMed
From Cancer Genomics to Precision Oncology-Tissue's Still an IssueCell, 2014, ISSN: 0092-8674 View on PubMed
Optimizing the treatment of BRAF mutant melanomaGenome Medicine, 2014, ISSN: 1756-994X View on PubMed
TORC1 Suppression Predicts Responsiveness to RAF and MEK Inhibition in BRAF-Mutant MelanomaScience Translational Medicine, 2013, ISSN: 1946-6234 View on PubMed
Bcl-2/Bcl-xL Inhibition Increases the Efficacy of Mek Inhibition Alone and in Combination with PI3 Kinase Inhibition in Lung and Pancreatic Tumor ModelsMolecular Cancer Therapeutics, 2013, ISSN: 1535-7163 View on PubMed
Synthetic Lethal Interaction of Combined BCL-XL and MEK Inhibition Promotes Tumor Regressions in KRAS Mutant Cancer ModelsCancer Cell, 2013, ISSN: 1535-6108 View on PubMed
Non-Covalent Wild-Type-Sparing Inhibitors of EGFR T790MCancer Discovery, 2012, ISSN: 2159-8274 View on PubMed
Genome and transcriptome sequencing of lung cancers reveal diverse mutational and splicing eventsGenome Research, 2012, ISSN: 1088-9051 View on PubMed
A phase I study of erlotinib and hydroxychloroquine in advanced non-small-cell lung cancerJournal of Thoracic Oncology, 2012, ISSN: 1556-0864 View on PubMed
Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitorsNature, 2012, ISSN: View on PubMed
Recent advances in pathway-targeted cancer drug therapies emerging from cancer genome analysisCurrent Opinion in Genetics & Development, 2012, ISSN: 0959-437X View on PubMed
The Q43L mutant of neuregulin 2β is a pan-ErbB receptor antagonistBiochemical Journal, 2012, ISSN: 0264-6021 View on PubMed
Identification of a mutation in the extracellular domain of the Epidermal Growth Factor Receptor conferring cetuximab resistance in colorectal cancerNature Medicine, 2012, ISSN: 1078-8956 View on PubMed
Androgen Deprivation Causes Epithelial-Mesenchymal Transition in the Prostate: Implications for Androgen-deprivation Therapy.Cancer Research, 22 Nov 2011, ISSN: 1538-7445. View on PubMed
Potential Therapeutic Strategies to Overcome Acquired Resistance to BRAF or MEK Inhibitors in BRAF Mutant CancersOncotarget, 2011, V2, N4, APR, pp 336-346. eISSN: 1949-2553.
Neuregulin-1-Mediated Autocrine Signaling Underlies Sensitivity to HER2 Kinase Inhibitors in a Subset of Human CancersCancer Cell, 16 Aug 2011, vol. 20, no. 2, p. 158-72, ISSN: 1878-3686. View on PubMed
Cancer: miRNA Addiction - Depending On Life's Little Things.Current Biology, 2010, ISSN: 1879-0445
- MIT, Cancer Biology, Postdoctoral Fellow – 1992
- Yale University, Human Genetics, Ph.D. – 1989
- University of Pennsylvania, Neuroscience, B.A. – 1983
Awards & Honors
- Martin Research Prize (MGH) – 2011
- AACR Team Science Award – 2010
- Laurel Schwartz Professorship – 2007
- V Foundation Translational Cancer Research Award – 2004
- Avon Foundation Award – 2003
- Samuel Waxman Cancer Research Foundation Award – 2003
- Bertucci Foundation Award – 2002
- Saltonstall Scholar Award – 2001
- American Cancer Society Junior Faculty Research Award – 1995
- American Cancer Society Institutional Research Award – 1993
- American Cancer Society Post-doctoral Fellowship – 1990
- NIH National Research Service Award – 1984