Abstract
Platinum chemotherapy remains the cornerstone of treatment for epithelial ovarian cancer (OC) and Poly (ADP-ribose) polymerase inhibitors (PARPi) now have an established role as maintenance therapy. The mechanisms of action of these agents is, in many ways, complementary, and crucially reliant on the intracellular DNA Damage Repair (DDR) response. Here, we review mechanisms of primary and acquired resistance to treatment with platinum and PARPi, examining the interplay between both classes of agents. A key resistance mechanism appears to be the restoration of the Homologous Recombination (HR) repair pathway, through BRCA reversion mutations and epigenetic upregulation of BRCA1. Alterations in non-homologous end-joint (NHEJ) repair, replication fork protection, upregulation of cellular drug efflux pumps, reduction in PARP1 activity and alterations to the tumour microenvironment have also been described. These resistance mechanisms reveal molecular vulnerabilities, which may be targeted to re-sensitise OC to platinum or PARPi treatment. Promising therapeutic strategies include ATR inhibition, epigenetic re-sensitisation through DNMT inhibition, cell cycle checkpoint inhibition, combination with anti-angiogenic therapy, BET inhibition and G-quadruplex stabilisation. Translational studies to elucidate mechanisms of treatment resistance should be incorporated into future clinical trials, as understanding these biologic mechanisms is crucial to developing new and effective therapeutic approaches in advanced OC.
Highlights
Epithelial Ovarian Cancer (EOC) is the seventh most common cancer in women and the leading cause of gynecologic cancer death worldwide [1]
Some form of HRD is likely to be present at baseline in more than 50% of high-grade serous ovarian cancers (HGSC) potentially underlying the initial sensitivity of this type of tumour to DNA damaging drugs, such as platinum chemotherapy [24]
Upregulation of Multidrug Resistance protein 1 (MDR1) has been described in an engineered Poly (ADP-ribose) polymerase inhibitors (PARPi)-resistant human ovarian cancer cell line [72], as a result of chromosomal translocations involving the ABCB1 gene [73]
Summary
Epithelial Ovarian Cancer (EOC) is the seventh most common cancer in women and the leading cause of gynecologic cancer death worldwide [1]. Standard front-line treatment for advanced EOC consists of cytoreductive surgery, with the goal of no residual disease (R0), and platinum-based chemotherapy [5]. Ribose Polymerase inhibitors (PARPi) have demonstrated impressive activity in the first [7,8,9] and second-line [10,11] maintenance settings. There is an urgent need to elucidate the mechanisms of platinum and PARPi resistance in EOC to improve patient stratification for therapeutic strategies that target molecular vulnerabilities to overcome treatment resistance. In both cases, mechanisms appear to be complex and inter-related. This article will review the literature regarding mechanisms of treatment resistance to platinum and PARPi in EOC and highlight planned strategies and clinical trials that may effectively re-sensitise tumours to these agents
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