Role of Chemotherapy and Mechanisms of Resistance to Chemotherapy in Metastatic Castration-Resistant Prostate Cancer

Abstract

Chemotherapy using the taxanes, docetaxel and cabazitaxel, remains an important therapeutic option in metastatic castration-resistant prostate cancer (CRPC). However, despite the survival benefits afforded by these agents, the survival increments are modest and resistance occurs universally. Efforts to overcome resistance to docetaxel by combining with biologic agents have heretofore been unsuccessful. Indeed, resistance to these taxanes is also associated with cross-resistance to the antiandrogen drugs, abiraterone and enzalutamide. Here, we discuss the various mechanisms of resistance to chemotherapy in metastatic CRPC and the potential role of emerging regimens and agents in varying clinical phases of development.

Chronic hypoxia‐induced slug promotes invasive behavior of prostate cancer cells by activating expression of ephrin‐B1

“…51,52 Although many novel agents designed to overcome chemoresistance are currently under development, the prognosis of castration-resistant cancers remains poor. 53 It is noteworthy that ephrin-B1 expression is strongly induced after ADT of prostate adenocarcinoma cells and, perhaps more importantly, ADT does not induce ephrin-B1 expression in normal tissue adjacent to the cancerous region. This suggests that ephrin-B1 may be a novel promising therapeutic target with a low risk of local toxicity in healthy tissue, in combination with ADT or as adjuvant treatment after ADT for aggressive prostate cancers.…”

“…Docetaxel has been used as the standard chemotherapeutic drug for metastatic castration‐resistant cancers, but resistance eventually occurs through a number of mechanisms, including activation of prosurvival signaling, increased drug‐efflux, and overexpression of β‐tubulin isoforms and inflammation‐associated molecules . Although many novel agents designed to overcome chemoresistance are currently under development, the prognosis of castration‐resistant cancers remains poor . It is noteworthy that ephrin‐B1 expression is strongly induced after ADT of prostate adenocarcinoma cells and, perhaps more importantly, ADT does not induce ephrin‐B1 expression in normal tissue adjacent to the cancerous region.…”

Treatment sequence in castration-resistant prostate cancer: A retrospective study in the new anti-androgen era

“…Furthermore, the situation is complicated by recent clinical trials that may lead to the early administration of DOC in combination with androgen-deprivation therapy, or to novel indications of AA and EZL in pre-DOC patients (13,14). In this setting, certain prior reports have indicated the possibility of the occurrence of cross-resistance when first-line chemotherapy with DOC was administered after the novel hormonal agent AA; by contrast, there have been few instances of DOC rechallenge following failure to respond to AA or other agents (15,16). The cross-resistance to AA and EZL, as well as EWS, has been attributed to the expression of an AR splice variant-7 (17,18).…”

AKR1C3 expression in primary lesion rebiopsy at the time of metastatic castration‐resistant prostate cancer is strongly associated with poor efficacy of abiraterone as a first‐line therapy

“…[1][2][3][4] However, these therapies are not always effective and drug-resistance inevitably develops through a variety of mechanisms. 5,6 Therefore, exploring biomarkers that can help with making treatment decisions are crucial for patients with mCRPC.…”