Abstract
Despite aggressive treatment for localized cancer, prostate cancer (PC) remains a leading cause of cancer-related death for American men due to a subset of patients progressing to lethal and incurable metastatic castrate-resistant prostate cancer (CRPC). Organ-confined PC is treated by surgery or radiation with or without androgen deprivation therapy (ADT), while options for locally advanced and disseminated PC include radiation combined with ADT, or systemic treatments including chemotherapy. Progression to CRPC results from failure of ADT, which targets the androgen receptor (AR) signaling axis and inhibits AR-driven proliferation and survival pathways. The exact mechanisms underlying the transition from androgen-dependent PC to CRPC remain incompletely understood. Reactivation of AR has been shown to occur in CRPC despite depletion of circulating androgens by ADT. At the same time, the presence of AR-negative cell populations in CRPC has also been identified. While AR signaling has been proposed as the primary driver of CRPC, AR-independent signaling pathways may represent additional mechanisms underlying CRPC progression. Identification of new therapeutic strategies to target both AR-positive and AR-negative PC cell populations and, thereby, AR-driven as well as non-AR-driven PC cell growth and survival mechanisms would provide a two-pronged approach to eliminate CRPC cells with potential for synthetic lethality. In this review, we provide an overview of AR-dependent and AR-independent molecular mechanisms which drive CRPC, with special emphasis on the role of the Jak2-Stat5a/b signaling pathway in promoting castrate-resistant growth of PC through both AR-dependent and AR-independent mechanisms.
Highlights
Recent epidemiological data identifies prostate cancer (PC) as the most common non-cutaneous cancer and the second-leading cause of cancer-related death among males in the United States following lung cancer [1]
Inhibition of Stat5a/b blocked primary growth of PC xenograft tumors, and recurrent growth of castrate-resistant tumors [177] demonstrated by pharmacological inhibition of Stat5a/b signaling by a potent Jak2 kinase inhibitor, AZD1480, in the CWR22Pc model of castrateresistant prostate cancer (CRPC) growth
Stat5a/b overexpression in DU145 cells increased colony formation in vitro and accelerated xenograft tumor growth in vivo [198]. These findings indicate that Stat5a/b acts through mechanisms operating independently of androgen receptor (AR) to promote growth of PC, in addition to mechanisms directly impacting AR function
Summary
Recent epidemiological data identifies prostate cancer (PC) as the most common non-cutaneous cancer and the second-leading cause of cancer-related death among males in the United States following lung cancer [1]. Binding of androgen ligands, such as testosterone and the more potent dihydrotestosterone (DHT), induces a conformational change in AR that allows for nuclear translocation and induction of androgen-responsive gene expression supporting growth and viability of prostate cells (reviewed in [32,33,34,35,36]). The overall contribution of AR-F876L to clinical resistance to second-generation antiandrogens remains to be determined; a genomic landscape study of 150 men with metastatic CRPC using next-generation sequencing did not detect the mutation, despite some patients previously receiving enzalutamide [68].
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