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Molecular determinants of chemotherapy resistance in ovarian cancer.

Resistance to chemotherapy is a major contributing factor in treatment failure and consequent mortality associated with cancer [1]. Traditionally, the drivers of chemotherapy resistance were discovered through genetic analysis of cancer cells by comparing the differences in gene expression between chemotherapy sensitive cells and chemotherapy-resistant counterparts made resistant by in vitro exposure to chemotherapeutic agents [1,2]. These studies provided a conceptual framework for wellrecognized mechanisms for chemotherapy resistance: namely pre-target resistance, on-target resistance, post-target resistance and off-target resistance [3]. Pre-target resistance is associated with several mechanisms that affect drug activity and bioavailability before it reaches the target. Pharmacokinetics, hypoxia and stromal composition that affect bioavailability of active drug at the target site could contribute to pre-target resistance. In addition, drug influx transporter, such as Ctr1, and efflux transporters, such as ATP7A and ATP7B, have been implicated in platinum resistance [4,5]. Other efflux transporters, such as MDR1 (P-gp) and MRP1, are also implicated in multidrug resistance [2,6–8]. Intracellular glutathione can alter the reactivity of cisplatin and enhance resistance to cisplatin [9]. Finally, recent whole genome tumor sequencing studies indicate that overexpression of MDR1, as a consequence of recurrent promoter fusion in high-grade serous ovarian cancer, is associated with acquired resistance to chemotherapy [10]. Alterations in the molecular target of the drug also contribute to on-target resistance. Cisplatin causes DNA lesions which are in turn recognized by several repair pathways, such as nuclear excision repair, base excision repair and homologous recombination repair. Consequently, defects in DNA repair pathway in cancer cells make them sensitive to cisplatin. However, reversion mutations in BRCA1 and BRCA2 that partially restore homologous recombination repair function are associated with resistance to cisplatin [10–12]. These mutations not only affect response to cisplatin but also sensitize the cells to PARP inhibitors [13]. Similarly, point mutations in the paclitaxel-binding sites on α-tubulin and β-tubulin and selective alterations in β-tubulin isotypes, such as the overexpression of class III β-tubulin, have been associated with paclitaxel resistance [14]. Post-target resistance results from multiple alterations within apoptotic pathways, as a result of defects in proapoptotic pathways and/or the aberrant activation of antiapoptotic pathways. One of the best-characterized modes of genotoxic action of cisplatin involves the mitochondrial apoptosis [15]. Consequently, alterations in the factors involved in regulation and execution of apoptosis have the potential to confer chemotherapy resistance [7]. Accumulating evidence have shown that upregulation of antiapoptotic factors such as Bcl–2, Bcl-xL, MCL–1, survivin and downregulation of proapoptotic factors, such as Bax and caspases, correlate with taxane and platinum-based c hemotherapy resistance [3,16–19]. FOXO1 Molecular determinants of chemotherapy resistance in ovarian cancer