Understanding the mechanisms of androgen deprivation resistance in prostate cancer at the molecular level

Abstract

Context: Various molecular mechanisms play a role in the development of resistance to androgen deprivation therapy in castration-resistant prostate cancer (CRPC).

Objective: To understand the mechanisms and biological pathways associated with the progression of prostate cancer (PCa) under systemic androgen depletion or administration of the novel antiandrogens abiraterone, enzalutamide, and ARN-509. This review also examines the introduction of novel combinational approaches for patients with CRPC.

Evidence acquisition: PubMed was the data source. Keywords for the search were castrate resistant prostate cancer, abiraterone, enzalutamide resistance mechanisms, resistance to androgen deprivation, AR mutations, amplifications, splice variants, and AR alterations. Papers published before 1990 were excluded from the review, and only English-language papers were included.

Evidence synthesis: This review summarizes the current literature regarding the mechanisms implicated in the development of CRPC and the acquisition of resistance to novel antiandrogen axis agents. The review focuses on androgen biosynthesis in the tumor microenvironment, androgen receptor (AR) alterations and post-transcriptional modifications, the role of glucocorticoid receptor, and alternative oncogenic signaling that is derepressed on maximum AR inhibition and thus promotes cancer survival and progression.

Conclusions: The mechanisms implicated in the development of resistance to AR inhibition in PCa are multiple and complex, involving virtually all classes of genomic alteration and leading to a host of selective/adaptive responses. Combinational therapeutic approaches targeting both AR signaling and alternative oncogenic pathways may be reasonable for patients with CRPC.

Patient summary: We looked for mechanisms related to the progression of PCa in patients undergoing hormonal therapy and treatment with novel drugs targeting the AR. Based on recent data, combining maximal AR inhibition with novel agents targeting other tumor-compensatory, non-AR-related pathways may improve the survival and quality of life of patients with castration-resistant PCa.

Keywords: Alternative signaling; Androgen receptor; Castration-resistant prostate cancer; Novel antiandrogens.

Figure 1

Paracrine and autocrine androgen biosynthesis as a mechanism of resistance to systemic androgen depletion. Upon systemic androgen deprivation the tumor microenvironment and prostate cancer cells produce androgens through androgen biosynthesis. In particular numerous steroidogenic enzymes (these enzymes are presented in red) implicated in the androgen biosynthesis are induced during the development of castrate resistant prostate cancer (CRPC). The novel agent Abiraterone Acetate (AA) targets the enzyme CYP17A1 and has been found to prolong the survival of patients with chemotherapy naïve and resistant prostate cancer.

Figure 2

Alternative oncogenic signaling implicated in the postranscriptional activation of AR. Upon androgen deprivation and AR inhibition numerous alternative oncogenic pathways are activated and promote the transcriptional activities of AR. Src and IL-6 signaling promote AR activation through MAPK signaling during the development of castration resistance. Moreover, IL-6 promotes the upregulation of TIF2, an AR co-regulator under androgen depletion. IL-6 and Akt signaling increase the interaction between p300 and AR increasing the stabilization of AR under low androgen levels. Finally, HER2 and HER3 downstream signaling has been associated with increased AR activity during prostate cancer progression.

Figure 3

Prostate cancer progression under androgen deprivation and AR inhibition. Systemic androgen depletion by hormonal therapy leads to progressive activation of numerous survival mechanisms including androgen biosynthesis in the tumor microenvironment while more effective AR inhibition through abiraterone, enzalutamide and ARN509 promotes the emergence of AR mutations, amplifications and variants maintaining disease progression. Finally, sustained AR inhibitions leads to alternative oncogenic signaling de-repression such as AKT, EZH2, STAT3 and c-Met and induction of Glucocorticoid receptor (GR) providing survival advantage to cancer cells under maximum AR inhibiton.