Abstract
Androgen deprivation therapy targeting the androgens/androgen receptor (AR) signaling continues to be the mainstay treatment of advanced-stage prostate cancer. The use of second-generation antiandrogens, such as abiraterone acetate and enzalutamide, has improved the survival of prostate cancer patients; however, a majority of these patients progress to castration-resistant prostate cancer (CRPC). The mechanisms of resistance to antiandrogen treatments are complex, including specific mutations, alternative splicing, and amplification of oncogenic proteins resulting in dysregulation of various signaling pathways. In this review, we focus on the major mechanisms of acquired resistance to second generation antiandrogens, including AR-dependent and AR-independent resistance mechanisms as well as other resistance mechanisms leading to CRPC emergence. Evolving knowledge of resistance mechanisms to AR targeted treatments will lead to additional research on designing more effective therapies for advanced-stage prostate cancer.
Highlights
Prostate cancer remains the most commonly diagnosed malignancy and the second leading cause of cancer related deaths among men in the United States[1]
Patients with metastatic castration-resistant prostate cancer (CRPC) exhibit poor prognosis and low predicted overall survival of less than 2 years from the initial time of progression; such patients account for a large portion of the prostate cancer-related deaths
Several studies demonstrated that PD-L1 is considerably expressed in enzalutamide-resistant cell lines and enzalutamide-resistant tumors in animal models[145]. These results suggest that CRPC progression and resistance to androgen receptor (AR) signaling pathways is facilitated by PD-L1 and PD-1[33]
Summary
Prostate cancer remains the most commonly diagnosed malignancy and the second leading cause of cancer related deaths among men in the United States[1]. Glucocorticoids initially have suppressive effects on prostate cancer and are often given in conjunction with early treatments of CRPC with chemotherapy and second-generation antiandrogen agents (enzalutamide or abiraterone acetate)[72] Both AR and GR possess similar DNA binding domain structures. Activation of AR-Vs mediated by heterogeneous nuclear RNA-binding protein (hnRPA-1) leads to significant hyperplasia and induced castration resistance growth[88] This leads to inhibition of apoptosis and cell cycle and limiting sensitivity to second-generation antiandrogen therapy. The epithelial-to-mesenchymal transition (EMT) is induced by ADT in metastatic prostate cancer, and studies demonstrate that this process promotes tumor progression and drug resistance[33] Activation of pathways such as TGF-β and SMAD alters the activity of some transcriptional factors such as Snail and Twist, reducing the expression of E-cadherin, a key event in EMT[129]. HDACs inhibitors are reported to inhibit genes involved in the formation T-E fusion transcript
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