Deciphering the mechanisms of PARP inhibitor resistance in prostate cancer: Implications for precision medicine

Abstract

Prostate cancer is a leading malignancy among men. While early-stage prostate cancer can be effectively managed, metastatic prostate cancer remains incurable, with a median survival of 3–5 years. The primary treatment for advanced prostate cancer is androgen deprivation therapy (ADT), but resistance to ADT often leads to castrationresistant prostate cancer (CRPC), presenting a significant therapeutic challenge. The advent of precision medicine has introduced promising new treatments, including PARP inhibitors (PARPi), which target defects in DNA repair mechanisms in cancer cells. PARPi have shown efficacy in treating advanced prostate cancer, especially in patients with metastatic CRPC (mCRPC) harboring homologous recombination (HR)-associated gene mutations. Despite these advancements, resistance to PARPi remains a critical issue. Here, we explored the primary mechanisms of PARPi resistance in prostate cancer. Key resistance mechanisms include homologous recombination recovery through reverse mutations in BRCA genes, BRCA promoter demethylation, and non-degradation of mutated BRCA proteins. The tumor microenvironment and overactivation of the base excision repair pathway also play significant roles in bypassing PARPi-induced synthetic lethality. In addition, we explored the clinical implications and therapeutic strategies to overcome resistance,emphasizing the need for precision medicine approaches. Our findings highlight the need for comprehensive strategies to improve PARPi sensitivity and effectiveness,ultimately aiming to extend patient survival and improve the quality of life for those with advanced prostate cancer. As our understanding of PARPi resistance evolves, more diverse and effective individualized treatment regimens will emerge.