Abstract
Critical DNA repair pathways become deranged during cancer development. This vulnerability may be exploited with DNA-targeting chemotherapy. Topoisomerase II inhibitors induce double-strand breaks which, if not repaired, are detrimental to the cell. This repair process requires high-fidelity functional homologous recombination (HR) or error-prone non-homologous end joining (NHEJ). If either of these pathways is defective, a compensatory pathway may rescue the cells and induce treatment resistance. Consistently, HR proficiency, either inherent or acquired during the course of the disease, enables tumor cells competent to repair the DNA damage, which is a major problem for chemotherapy in general. In this context, c-Abl is a protein tyrosine kinase that is involved in DNA damage-induced stress. We used a low-dose topoisomerase II inhibitor mitoxantrone to induce DNA damage which caused a transient cell cycle delay but allowed eventual passage through this checkpoint in most cells. We show that the percentage of HR and NHEJ efficient HeLa cells decreased more than 50% by combining c-Abl inhibitor imatinib with mitoxantrone. This inhibition of DNA repair caused more than 87% of cells in G2/M arrest and a significant increase in apoptosis. To validate the effect of the combination treatment, we tested it on commercial and patient-derived cell lines in high-grade serous ovarian cancer (HGSOC), where chemotherapy resistance correlates with HR proficiency and is a major clinical problem. Results obtained with HR-proficient and deficient HGSOC cell lines show a 50–85% increase of sensitivity by the combination treatment. Our data raise the possibility of successful targeting of treatment-resistant HR-proficient cancers.
Highlights
DNA damage repair (DDR) plays a critical role in the maintenance of genomic stability
We previously found that c-Abl inhibition after MX results in increased DNA cometing indicative of elevated DNA damage and massive cell death in cancer cells
Adding IM to MX significantly reduced nuclear RAD51 expression in Hela, BRCA1-wt MDA-MB-231, and BRCA1-silenced MDA-MB-231 cells. These findings suggest that the effects of concurrent inhibition of c-Abl and topoisomerase II are independent of BRCA1 status and depict a major role for c-Abl in DNA repair in these cancer cells
Summary
DNA damage repair (DDR) plays a critical role in the maintenance of genomic stability. An appropriate response to genotoxic drugs is required for cancer cell survival. Targeting this response has become an active area of research in the field of developing new cancer therapies. DNA damage alerts surveillance networks that stall cell cycle, allowing time for DNA repair. DNA repair involves mainly six pathways, including mismatch repair, homologous recombination repair, non-homologous end joining, trans-lesion DNA synthesis, base excision repair, and nucleotide excision [4]. The most common pathways to repair double-stranded breaks (DSBs) are non-homologous end joining (NHEJ) and homologous recombination (HR). NHEJ is error-prone and active throughout the cell cycle, whereas HR is a high-fidelity repair mechanism limited to the S and G2 phases of the cell cycle after genotoxic stress [5]
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