Abstract: Series 108, Lecture 3
The Harvey Lectures Series 108 (2012—2013)
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Lecture #3: Thursday, January 17, 2013 — Watch Video of Lecture
Overcoming Resistance to Cancer Drug Therapy
Charles L Sawyers, MD
Investigator, Howard Hughes Medical Institute
Chair, Human Oncology and Pathogenesis Program
Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center
New York, New York
My laboratory studies molecular drivers of cancer progression and strategies to overcome drug resistance. I first developed this interest during our studies of ABL kinase inhibitors in chronic myeloid leukemia, where we discovered that resistance to imatinib is caused by point mutations in BCR-ABL and that the second generation drug dasatinib can overcome much of this resistance. A collaboration with John Kuriyan’s group (UC Berkeley) was instrumental in this success by providing a structural understanding of distinct conformations of the ABL kinase domain bound by imatinib and dasatinib and the impact of missense mutations on these conformations. More recently my group has explored the molecular basis of resistance to hormone therapy in prostate cancer, which led to the discovery of a novel antiandrogen called enzalutamide (formerly MDV3100) that prolongs survival in men with castration resistant prostate cancer. Despite its impressive clinical benefit, enzalutamide is not effective in all patients. Roughly half of men with metastatic CRPC do not have meaningful responses, and half of the men who do respond develop resistance within 1-2 years. Current efforts are focused on understanding this heterogeneity in clinical response and developing next generation treatment strategies.