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.
Highlights
The development of drug resistance represents one of the major obstacles to the cure of cancer.in many instances, tumors that are initially responsive to a given drug will relapse with a tumor no longer sensitive to the initial drug
In spite of the evidence suggesting that the different types of epithelial ovarian cancer (EOC) represent unique entities, they are still treated with a similar approach consisting of a de-bulking surgery followed by adjuvant chemotherapy
Secondary somatic mutations in RAD51C and RAD51D genes restoring the reading frame of the proteins have been reported in post-progression tumor samples obtained from patients participating in ARIEL2 Part1 clinical trial, in which patients with platinum-sensitive, relapsing tumor were treated with the PARP inhibitor rucaparib
Summary
The development of drug resistance represents one of the major obstacles to the cure of cancer. Epithelial ovarian cancer is one of the most chemo-responsive tumors responding well to both cisplatin and carboplatin, almost invariably after an initial response, patients will relapse with platinum resistant tumors. Resistance to platinum-containing drugs has been associated to several mechanisms, including alteration in drug efflux (through for example the modulation of the copper transporter CTR-1 expression) [1,2,3,4,5], alteration in intracellular proteins able to bind and sequester Pt (as for example GSH) [6,7,8,9], and altered. We will here focus on DNA repair pathways as possible mechanism of resistance to a platinum-based therapy in ovarian cancer. The importance of predictive biomarkers of response to platinum will be described with the aim to possibly identify patients that will not respond to therapy and could eventually be re-directed to alterative therapeutic strategies
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