Platinum Resistance in Ovarian Cancer: Role of DNA Repair

Abstract

Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer. It is initially responsive to cisplatin and carboplatin, two DNA damaging agents used in first line therapy. However, almost invariably, patients relapse with a tumor resistant to subsequent treatment with platinum containing drugs. Several mechanisms associated with the development of acquired drug resistance have been reported. Here we focused our attention on DNA repair mechanisms, which are fundamental for recognition and removal of platinum adducts and hence for the ability of these drugs to exert their activity. We analyzed the major DNA repair pathways potentially involved in drug resistance, detailing gene mutation, duplication or deletion as well as polymorphisms as potential biomarkers for drug resistance development. We dissected potential ways to overcome DNA repair-associated drug resistance thanks to the development of new combinations and/or drugs directly targeting DNA repair proteins or taking advantage of the vulnerability arising from DNA repair defects in EOCs.

Keywords: DNA damage response; DNA damaging agents; DNA polymorphisms; DNA repair; cisplatin; drug resistance; gene mutations; homologous recombination; nucleotide excision repair; ovarian cancer.

Figure 1

Schematic representation of the major pathways involved in DNA damage recognition and repair of platinum DNA damage. The major proteins acting as sensors and effectors of the DNA damage are reported. According to the tumor cell ability to repair the damage, cells will survive and acquired resistance to treatment or not repair and die.