Pathways of chemotherapy resistance in castration-resistant prostate cancer

Abstract

Chemotherapy remains the major treatment option for castration-resistant prostate cancer (CRPC) and limited cytotoxic options are available. Inherent chemotherapy resistance occurs in half of all patients and inevitably develops even in those who initially respond. Docetaxel has been the mainstay of therapy for 6 years, providing a small survival benefit at the cost of significant toxicity. Cabazitaxel is a promising second-line agent; however, it is no less toxic, whereas mitoxantrone provides only symptomatic benefit. Multiple cellular pathways involving apoptosis, inflammation, angiogenesis, signalling intermediaries, drug efflux pumps and tubulin are implicated in the development of chemoresistance. A thorough understanding of these pathways is needed to identify biomarkers that predict chemotherapy resistance with the aim to avoid unwarranted toxicities in patients who will not benefit from treatment. Until recently, the search for predictive biomarkers has been disappointing; however, the recent discovery of macrophage inhibitory cytokine 1 as a marker of chemoresistance may herald a new era of biomarker discovery in CRPC. Understanding the interface between this complex array of chemoresistance pathways rather than their study in isolation will be required to effectively predict response and target the late stages of advanced disease. The pre-clinical evidence for these resistance pathways and their progress through clinical trials as therapeutic targets is reviewed in this study.

Monensin Induced Oxidative Stress Reduces Prostate Cancer Cell Migration and Cancer Stem Cell Population

“…NF-κB inhibitors are known to decrease AR signalling in vitro and reduce the growth of androgen deprivation-resistant prostate cancer xenografts in vivo (Jin et al 2008, Zhang et al 2009b. However, at present no specific NF-κB inhibitors have reached the stage of clinical trials for prostate cancer treatment (Mahon et al 2011). Our results support NF-κB as the main mediator of monensin induced oxidative stress, which may also contribute to the reduced androgen signalling and induction of apoptosis in monensin exposed prostate cancer cells.…”

Increased expression of Lgr5 is associated with chemotherapy resistance in human gastric cancer

“…Furthermore, many signaling pathways have been associated with chemotherapy resistance, including the Wnt signaling pathway (36)(37)(38)(39)(40). Previous studies indicated that dysregulation of the Wnt/β-catenin signaling pathway is involved in pancreatic cancer chemoresistance (39).…”

Restoration of fibroblast growth factor receptor 2IIIb enhances the chemosensitivity of human prostate cancer cells

“…Docetaxel functions as an inhibitor of microtubular depolymerization (30). In addition to microtubular dynamics, multiple cellular pathways involving apoptosis, inflammation, angiogenesis, signaling intermediaries, and drug efflux pumps have been implicated in the chemosensitivity of docetaxel (31). Previous and present data indicate that the FGFR2IIIb signaling pathway induces apoptosis and furthermore might suppress EMT or at least reverse it, which has been reported to prevent the apoptosis of cancer cells and to induce resistance to chemotherapy (29,32).…”

“…4. Survivin and XIAP are a family of inhibitors of apoptosis proteins (IAPs) that promote cell survival by inhibiting the caspase cascade and apoptosis (31,33). Survivin and XIAP are the most studied IAPs with regard to resistance to anticancer agents.…”