Overcoming Platinum and PARP-Inhibitor Resistance in Ovarian Cancer

Title	Overcoming Platinum and PARP-Inhibitor Resistance in Ovarian Cancer
Authors	Michelle McMullen, Katherine Karakasis, Ainhoa Madariaga, Amit M. Oza
Magazine	Cancers
Date	06/17/2020
DOI	https://doi.org/10.3390/cancers12061607
Introduction	Platinum chemotherapy remains the mainstay in treating epithelial ovarian cancer, while Poly (ADP-ribose) polymerase inhibitors (PARPi) have gained prominence as maintenance therapy. These agents rely heavily on the intracellular DNA Damage Repair (DDR) response, with mechanisms of action that complement each other. This review delves into both primary and acquired resistance mechanisms to platinum and PARPi treatments, focusing on the interaction between these therapies. A central resistance mechanism is the restoration of the Homologous Recombination (HR) repair pathway via BRCA reversion mutations and BRCA1 epigenetic upregulation. Additional resistance factors include changes in non-homologous end-joining (NHEJ) repair, replication fork protection, cellular drug efflux pump upregulation, reduced PARP1 activity, and tumour microenvironment alterations. These mechanisms highlight molecular vulnerabilities that can be targeted to re-sensitise ovarian cancer to platinum or PARPi therapy. Promising therapeutic strategies involve ATR inhibition, epigenetic re-sensitisation through DNMT inhibition, cell cycle checkpoint inhibition, combination with anti-angiogenic therapy, BET inhibition, and G-quadruplex stabilisation. Future clinical trials incorporating translational studies to understand resistance mechanisms are vital for developing new and effective therapeutic strategies in advanced ovarian cancer.
Quote	Michelle McMullen, Katherine Karakasis and Ainhoa Madariaga et al. Overcoming Platinum and PARP-Inhibitor Resistance in Ovarian Cancer. Cancers (Basel). 2020. Vol. 12(6). DOI: 10.3390/cancers12061607
Element	Platinum (Pt)
Industry	Pharmaceutical Industry , Medical Devices , Pharmaceuticals & Cosmetics