Revisiting chemoresistance in ovarian cancer: Mechanism, biomarkers, and precision medicine

Abstract

Among the gynecological cancers, ovarian cancer is the most lethal. Its therapeutic options include a combination of chemotherapy with platinum-based compounds and cytoreductive surgery. Most ovarian cancer patients exhibit an initial response to platinum-based therapy, however, platinum resistance has led to up to 80% of this responsive cohort becoming refractory. Ovarian cancer recurrence and drug resistance to current chemotherapeutic options is a global challenge. Chemo-resistance is a complex phenomenon that involves multiple genes and signal transduction pathways. Therefore, it is important to elucidate on the underlying molecular mechanisms involved in chemo-resistance. This inform decisions regarding therapeutic management and help in the identification of novel and effective drug targets. Studies have documented the individual biomarkers of platinum-resistance in ovarian cancer that are potential therapeutic targets. This review summarizes the molecular mechanisms of platinum resistance in ovarian cancer, novel drug targets, and clinical outcomes.

Keywords: Clinical outcomes; Mechanisms; Molecular biomarkers; Ovarian cancer; Platinum resistance.

Figure 1

Single stranded DNA breaks (ssDNA) can be repaired by PARP pathway. PARP inhibitor (PARPi) treatment restrain PARP repairing ssDNA and lead to double-stranded DNA (dsDNA) breaks which then undergo homologous recombination (HR). When coming to DNA repair via HR pathway, BRCA mutated cells are unable to undergo and lead to cell death. Both PARP inhibition and BRCA mutation are needed for cell death. In case of defects of both HR and NHEJ, inhibition of PARP restrains activation of alternative NHEJ (Alt-EJ) which contributes to dsDNA repairment when NHEJ components are missing. With the formation of PARP-DNA complexes PARP trapping may occur restraining DNA replication and transcription. But PARP inhibitors' trapping ability varies significantly.