Cancer Drug Resistance: Challenges and Opportunities

Cancer resistance to molecularly targeted therapies is a major problem facing researchers. Such resistance can occur when mutations or other genetic alterations restore a signaling pathway downstream of the pathway targeted by the therapy.

In this lecture, Dr. Charles Sawyers will discuss this important area of research using prostate cancer as an example. Recent evidence, for instance, suggests that while more potent inhibitors deliver superior clinical efficacy, they can lead to more diverse mechanisms for cancer cells to escape treatment. Prostate cancers treated with the drug enzalutamide can develop resistance through mutations in the androgen receptor, via bypass of the androgen receptor blockade by signaling through the glucocorticoid receptor, or by lineage plasticity. During lineage plasticity, androgen-dependent luminal epithelial cells undergo an identity change to more basal-like epithelial cells. The complexity underlying these adaptive responses to targeted therapy reinforces the importance of combination therapy to achieve long-term clinical benefit.