Androgen pathway resistance in prostate cancer and therapeutic implications

Abstract

Introduction Metastatic prostate cancer is an incurable disease that is treated with a variety of hormonal therapies targeting various nodes of the androgen receptor (AR) pathway. Invariably patients develop resistance and become castration resistant. Common treatments for castration-resistant disease include novel hormonal therapies, such as abiraterone and enzalutamide, chemotherapy, immunotherapy and radiopharmaceuticals. As this disease generally remains incurable, understanding the molecular underpinnings of resistance pathways is critical in designing therapeutic strategies to delay or overcome such resistance. Areas covered This review will explore the resistance mechanisms relevant to hormonal agents, such as AR-V7 expression and others, as well as discussing new approaches being developed to treat patients with castration-resistant prostate cancer that take advantage of these new insights. A literature search was performed to identify all published clinical trials related to androgen therapy mechanisms of drug resistance in metastatic castration-resistant prostate cancer. Expert opinion Androgen therapy resistance mechanisms are varied, and include modification of all nodes in the androgen signaling pathway. The optimal treatment for men with relapsed metastatic castration-resistant prostate cancer is uncertain at this time. The authors recommend using available clinical data to guide treatment decision making until more specific biomarkers are clinically available.

Co-targeting AR and HSP90 suppresses prostate cancer cell growth and prevents resistance mechanisms

“…1), as therapeutic doses of Hsp90 inhibitors and AR antagonists are known to induce mechanisms of resistance (Centenera et al 2012, Maughan & Antonarakis 2015. Combination of these sub-optimal doses of 17-AAG and bicalutamide significantly inhibited the proliferation and induced death of LNCaP (P!0.05; Fig.…”

“…Despite an initial response to ADT, the majority of patients will inevitably progress to castrate-resistant prostate cancer (CRPC) that is not curable by current treatments. CRPC develops as prostate cancer cells adapt to a low androgen environment through a range of resistance mechanisms that are predominantly mediated by alterations to androgen receptor (AR) signaling (Karantanos et al 2013, Maughan & Antonarakis 2015. These include AR overexpression or amplification (Chen et al 2008), acquisition of gain-of-function point mutations in the AR gene (Buchanan et al 2001), intra-tumoral androgen biosynthesis (Cai & Balk 2011) or emergence of C-terminally truncated AR variants (ARVs) that are constitutively nuclear and active (Sun et al 2010, Li et al 2011.…”

Exploring the optimal sequence of abiraterone and enzalutamide in patients with chemotherapy‐naïve castration‐resistant prostate cancer: The Kyoto‐Baltimore collaboration

“…There are no reports yet that directly compare the efficacy of these two agents, although there are several retrospective studies showing the decreased efficacy of the second‐line AR‐targeting therapy after progression on the first‐line therapy . This suggests that there are shared mechanisms of resistance between ABI and ENZA, such as AR‐V7 splice variant expression and activating AR mutations as well as others. 12,13…”

Flightless I Homolog Represses Prostate Cancer Progression through Targeting Androgen Receptor Signaling

“…Therefore, potent antiandrogens that efficiently disrupt the functions (signaling) of AR are envisioned to be effective drugs for all types of prostate cancers (11). Blocking AR expression and activation has become one of the most effective therapies in clinical management of this disease (12).…”