Hormone Therapy for Prostate Cancer
1Memorial Sloan Kettering Cancer Center, New York, NY, USA
Resistance to molecularly targeted cancer therapies often occurs through mutations/genomic alterations that restore signaling downstream of the targeted pathway. Using prostate cancer as an example, I will review recent evidence that more potent inhibitors, which can clearly deliver superior clinical efficacy, can lead to more diverse mechanisms of escape. Prostate cancers treated with the novel antiandrogen enzalutamide can develop resistance through mutations in the androgen receptor, through bypass of androgen receptor blockade by signaling through the glucocorticoid receptor or by lineage plasticity, whereby androgen-dependent luminal epithelial cells undergo an identity change to more basal-like epithelial cells. The molecular basis for these resistance mechanisms includes genetic as well as epigenetic changes which point to new strategies to overcome resistance. These findings reveal the complexity underlying adaptive responses to targeted therapy and reinforce the importance of combination therapy to achieve long term clinical benefit.