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Charles L. Sawyers: Overview

Overcoming Resistance to Molecularly Targeted Cancer Therapy

Our laboratory is focused on characterizing signal transduction pathway abnormalities in various cancers with an eye toward translational implications. One example is chronic myeloid leukemia (CML) which is caused by the BCR-ABL fusion gene, expressed as a consequence of the Philadelphia chromosome translocation. In collaboration with Brian Druker at Oregon Health Sciences University, we developed the ABL kinase inhibitor imatinib/Gleevec as primary therapy for patients with CML. Shortly thereafter, my group discovered that resistance to imatinib is caused by BCR-ABL kinase domain mutations. We worked closely with John Kuriyan’s group to examine the structural consequences of these mutations on the ABL kinase domain and postulated that second generation ABL kinase inhibitors that bind to ABL differently from imatinib might retain activity against imatinib-resistant mutants. In collaboration with scientists at Bristol Myers Squibb, we showed that the dual Src/Abl inhibitor dasatinib has such properties in preclinical models, then co-led the clinical development of dasatinib as treatment for imatinib-resistant CML. Subsequently, we found that dasatinib resistance occurs through additional, novel BCR-ABL mutations, some of which remain sensitive to imatinib, making a strong case for combined ABL kinase inhibitor treatment to prevent the emergence of resistant subclones.

A second project in my group explores the molecular basis of prostate cancer and mechanisms of resistance to hormone therapy. This work is currently focused on the role of the androgen receptor in disease progression, even when tumors progress to the hormone-refractory stage. After demonstrating that higher levels of androgen receptor are necessary and sufficient to confer resistance to current antiandrogens, we collaborated with UCLA chemist Michael Jung to discover a small molecule inhibitor that targets the increased levels of androgen receptor found in hormone refractory disease by a novel mechanism. A phase I-II trial of this compound (MDV3100), now underway at MSK and other sites, has shown impressive clinical responses in men with castrate-resistant prostate cancer, including those who have progressed on chemotherapy. MDV3100 will undergo phase III clinical testing beginning in 2009. Current projects are deciphering mechanisms of resistance to MDV3100, dissecting AR function using RNA interference screens and examining crosstalk between AR and other common molecular lesions in human prostate cancer such as PTEN loss and TMPRSS2-ERG gene fusions.

Requests for LAPC4 or LAPC9 cells should be directed to Dr. Robert Reiter at UCLA. For further information, contact his lab manager, Joyce Yamashiro, at JYamashiro@mednet.ucla.edu.

Requests for Myc-CaP cell lines should be directed to ATCC. The order number at ATTC is Myc-CaP cell line (ATCC® CRL-3255™).

About Charles Sawyers

Charles L. Sawyers received a BA from Princeton University in 1981 and an MD from Johns Hopkins University School of Medicine in 1985, followed by an internal medicine residency at the University of California, San Francisco. He became a Howard Hughes Medical Institute investigator in 2002 while at the University of California, Los Angeles, and then moved to Memorial Sloan Kettering in 2006, where he currently serves as the Chair of the Human Oncology and Pathogenesis Program.

Dr. Sawyers studies mechanisms of cancer drug resistance with an eye toward developing novel therapies. He co-discovered the antiandrogen drug enzalutamide that was approved by the FDA in 2012 for the treatment of advanced prostate cancer. He shared the 2009 Lasker~DeBakey Clinical Medical Research Award for the development of the ABL kinase inhibitor imatinib for patients with chronic myeloid leukemia and the second-generation ABL inhibitor dasatinib to overcome imatinib resistance. He received the 2013 Breakthrough Prize in Life Sciences, the 2013 Taubman Prize for Excellence in Translational Medical Science, and the 2015 BBVA Knowledge Award in Biomedicine.

Dr. Sawyers is a member of the National Academy of Sciences, the National Academy of Medicine, and the American Academy of Arts and Sciences. He is past president of the American Association for Cancer Research (AACR) and the American Society of Clinical Investigation, was appointed to the National Cancer Advisory Board by President Obama, and has served on the Board of Directors of Novartis since 2013. He also serves as Steering Committee Chair of AACR Project GENIE, an international consortium of cancer centers that share genomic and clinical data from patients treated at their respective clinical sites.

Disclosure Statement

Dr. Sawyers serves on the Board of Directors of Novartis and is a co-founder of ORIC Pharm and co-inventor of enzalutamide and apalutamide. He is a science advisor to Agios Pharmaceuticals, BeiGene, Blueprint Medicines, The Column Group, Foghorn Therapeutics, Housey Pharmaceuticals, Nextech, KSQ Therapeutics, Petra Pharma Corporation, and PMV Pharma. He was a co-founder of Seragon Pharmaceuticals, purchased by Genentech/Roche in 2014.