Targeting molecular resistance in castration-resistant prostate cancer

Abstract

Multiple mechanisms of resistance contribute to the inevitable progression of hormone-sensitive prostate cancer to castration-resistant prostate cancer (CRPC). Currently approved therapies for CRPC include systemic chemotherapy (docetaxel and cabazitaxel) and agents targeting the resistance pathways leading to CRPC, including enzalutamide and abiraterone. While there is significant survival benefit, primary and secondary resistance to these therapies develops rapidly. Up to one-third of patients have primary resistance to enzalutamide and abiraterone; the remaining patients eventually progress on treatment. Understanding the mechanisms of resistance resulting in progression as well as identifying new targetable pathways remains the focus of current prostate cancer research. We review current knowledge of mechanisms of resistance to the currently approved treatments, development of adjunctive therapies, and identification of new pathways being targeted for therapeutic purposes.

Fig. 1

Androgen receptor-dependent mechanisms of resistance in hormone-naïve prostate cancer leading to castration-resistance, and role of current FDA-approved therapies. wtAR, Wild-type androgen receptor; ARV, Androgen receptor variant; mutAR, Mutated androgen receptor; T, Testosterone; DHT, Dihydrotestosterone

Fig. 2

Androgen synthesis pathway. Reproduced with permission from Clinical Cancer Research [68]