Abstract
In recent years, many therapeutic advances have been made in the management of castration-resistant prostate cancer, with the development and approval of many new drugs. The androgen receptor (AR) is the main driver in prostate cancer growth and progression and the most effective therapeutic agents are still directed against this pathway. Among these, new generation hormonal agents (NHA) including enzalutamide, abiraterone acetate, apalutamide, and darolutamide have shown to improve overall survival and quality of life of prostate cancer patients. Unfortunately, despite the demonstrated benefit, not all patients respond to treatment and almost all are destined to develop a resistant phenotype. Although the resistance mechanisms are not fully understood, the most studied ones include the activation of both dependent and independent AR signalling pathways. Recent findings about multiple growth-promoting and survival pathways in advanced prostate cancer suggest the presence of alternative mechanisms involved in disease progression, and an interplay between these pathways and AR signalling. In this review we discuss the possible mechanisms of primary and acquired resistance to NHA with a focus on AR independent pathways.
Highlights
Prostate cancer (PC) is the most frequent cancer in men and accounts for almost 1 in 5 new diagnoses. in recent years there has been a decrease in mortality due to earlier detection and advances in treatment, PC is still the second leading cause of cancer death among men in the USA[1]
androgen receptor (AR) amplification/overexpression is the most common genomic aberration in castration-resistant prostate cancer (CRPC) patients; up to 80% of these patients show AR overexpression[30]. This type of adaptation is more common in patients who progressed during new generation hormonal therapy than in treatment-naïve patients, so it has been considered as a potential resistance mechanism[31]
Many efforts have been made to investigate the genomic landscape of PC
Summary
Prostate cancer (PC) is the most frequent cancer in men and accounts for almost 1 in 5 new diagnoses. NHA: new generation hormonal agents; mCRPC: metastatic castration resistant prostate cancer, OS: overall survival; mo: months; HR: hazard ratio; CI: confidence interval; rPFS: radiographic progression free survival; est: estimated; MFS: metastasis free survival; mCSPC: metastatic Castration sensitive prostate cancer. Despite the significant T levels decrease induced by ADT, CRPC remains driven by AR signaling[23]; PC cells are able to synthesize androgens and modify AR, enabling it to activate even in the presence of low levels of androgens The mechanisms underlying this phenomenon are associated with the selective pressure of ADT and include AR gene overexpression, AR gene mutation, AR splice variants expression, and upregulation of transcriptional coactivators[24]. Adaptive resistance of PC to abiraterone and enzalutamide treatment is much better understood, and it can be due to the activation of both dependent and independent AR signalling pathways[26,29]
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