Targeting MRE11 Overcomes Platinum Resistance and Enhances Radiosensitivity in Non-Small Cell Lung Cancer Cells

Abstract Purpose Concomitant cisplatin (CP)-based chemo-radiotherapy is a standard-of-care regimen for non-small cell lung cancer (NSCLC), but intrinsic and acquired resistance to CP and ionizing radiation (IR) severely limits clinical efficacy. The MRN complex is essential for DNA double-strand break (DSB) repair and coordinates the cellular response to both IR-induced lesions and CP-mediated crosslinks. This study investigated the interaction between CP-induced adduct formation and IR-driven DSBs, evaluating whether inhibiting the MRE11 subunit of the MRN complex can selectively reverse resistance and enhance chemo-radiosensitivity in platinum-resistant NSCLC. Methods A panel of nine NSCLC cell lines and two non-transformed human dermal fibroblast models were examined. Cellular responses to CP, IR, or their combination were evaluated via clonogenic survival and cell cycle analysis. Pt-GpG crosslink kinetics were quantified, and the DNA damage response (DDR) was monitored by tracking gH2AX, 53BP1, and RAD51 foci formation. Pharmacological MRE11 inhibition was achieved using the small-molecule inhibitor mirin. Results Based on 72-hour half-maximal inhibitory concentrations, IC50, NSCLC lines were stratified into CP-sensitive (IC50≤ 2µM) and CP-resistant (IC50> 2µM) cohorts. CP significantly enhanced the radiosensitivity of the most CP sensitive cell lines, without an effect on radiosensitivity cell lines resistant for cisplatin. Initial Pt-GpG adduct burden did not correlate with baseline CP sensitivity. While CP triggered S- and G2/M-phase arrest across all lines, mirin selectively enhanced the radiosensitivity of CP-resistant NSCLC cells (A549, H1299, H838, H520, and H23; with the exception of H1975). Mechanistically, mirin significantly elevated Pt-GpG adduct retention and disrupted downstream DDR signaling (53BP1 and RAD51 foci formation) in these resistant tumor cells. In stark contrast, mirin significantly reduced adduct accumulation and slightly increased post-irradiation survival in normal fibroblasts, leaving their primary DDR signaling intact. Conclusions MRE11 inhibition via mirin selectively disrupts DDR signaling and promotes cisplatin-adduct retention in platinum-resistant NSCLC cells while sparing non-transformed tissues. These findings establish MRE11 as a promising therapeutic target to overcome chemo-radioresistance in refractory lung carcinomas while protecting normal cells.