Molecular mechanisms underlying resistance to androgen deprivation therapy in prostate cancer

Abstract

Prostate cancer (PCa) is the most widely diagnosed male cancer in the Western World and while low- and intermediate-risk PCa patients have a variety of treatment options, metastatic patients are limited to androgen deprivation therapy (ADT). This treatment paradigm has been in place for 75 years due to the unique role of androgens in promoting growth of prostatic epithelial cells via the transcription factor androgen receptor (AR) and downstream signaling pathways. Within 2 to 3 years of ADT, disease recurs—at which time, patients are considered to have castration-recurrent PCa (CR-PCa). A universal mechanism by which PCa becomes resistant to ADT has yet to be discovered. In this review article, we discuss underlying molecular mechanisms by which PCa evades ADT. Several major resistance pathways center on androgen signaling, including intratumoral and adrenal androgen production, AR-overexpression and amplification, expression of AR mutants, and constitutively-active AR splice variants. Other ADT resistance mechanisms, including activation of glucocorticoid receptor and impairment of DNA repair pathways are also discussed. New therapies have been approved for treatment of CR-PCa, but increase median survival by only 2-8 months. We discuss possible mechanisms of resistance to these new ADT agents. Finally, the practicality of the application of “precision oncology” to this continuing challenge of therapy resistance in metastatic or CR-PCa is examined. Empirical validation and clinical-based evidence are definitely needed to prove the superiority of “precision” treatment in providing a more targeted approach and curative therapies over the existing practices that are based on biological “cause-and-effect” relationship.

Activation of Notch pathway is linked with epithelial-mesenchymal transition in prostate cancer cells

“…[5][6][7][8] Recently, Notch signaling pathway was characterized as a potential driver in prostate cancer development. 9,10 Notch receptors (Notch 1-Notch 4) and their ligands (Jagged-1, Jagged-2, Delta-1, Delta-3, and Delta-4) have been identified.…”

Mechanistic Study of Inhibitory Effects of Metformin and Atorvastatin in Combination on Prostate Cancer Cells <i>in Vitro</i> and <i>in Vivo</i>

“…Unfortunately, almost all patients treated with androgen deprivation therapy will progress to castration-resistant prostate cancer (CRPC). 2,3) Docetaxel is the most commonly prescribed first-line chemotherapy for CRPC. 4) Although docetaxel provides a modest (2.4-month) increase in median overall survival, many patients with CRPC cannot tolerate this cytotoxic chemotherapy due to advanced age, medical comorbidities, or limited bone marrow reserves.…”

Fighting tubulin-targeting anticancer drug toxicity and resistance

“…As illustrated in Fig. 1, acquired resistance is mostly the result of AR gene amplification or of point mutations and expression of splice variants coding for more sensitive, less specific or constitutively active AR proteins (Wadosky & Koochekpour 2016). Recently, many new treatments have been approved for therapy of castration-resistant prostate cancer (CRPC).…”

“…Three main mechanisms of resistance to androgen deprivation therapy related to androgen receptor (AR) are depicted. Other mechanisms of resistance have been described, such as androgen-independent activation of AR mediated by oncogenic signaling (see text and Wadosky & Koochekpour 2016). (A) Castration-resistant prostate cells overexpress AR because of gene amplification; (B) point mutated ARs are constitutively active; (C) AR splice variants are ligand independent.…”