Elevated Expression of the RAGE Variant-V in SCLC Mitigates the Effect of Chemotherapeutic Drugs

Simple Summary Radiomimetic drugs induce extensive genotoxic insults to their target cells. Irreparable DNA damage leaves cells with the choice between a program leading to cell death or senescence, but not DNA repair. Among the challenges of an advanced stage of small cell lung carcinoma (SCLC), the resistance to radiomimetic drugs is the most prominent one. In SCLC, the initial chemotherapeutic treatment primes cell to modify their DNA repair and cell cycle regulatory systems, using alternative but highly efficient forms of DNA repair and auxiliary factors. This modulated system now bypasses several regulatory controls. Thus, at this stage, cells become resistant to any beneficial effects of chemotherapeutic drugs. In the present study, we observed that variant-V of the receptor for advanced glycation end-products (RAGE) is abundantly expressed in advancing and metastasizing SCLC. Therefore, it may serve as a potential target for specific therapeutic interventions directed to SCLC. Small cell lung carcinoma (SCLC) is a highly aggressive malignancy with a very high mortality rate. A prominent part of this is because these carcinomas are refractory to chemotherapies, such as etoposide or cisplatin, making effective treatment almost impossible. Here, we report that elevated expression of the RAGE variant-V in SCLC promotes homology-directed DNA DSBs repair when challenged with anti-cancer drugs. This variant exclusively localizes to the nucleus, interacts with members of the double-strand break (DSB) repair machinery and thus promotes the recruitment of DSBs repair factors at the site of damage. Increased expression of this variant thus, promotes timely DNA repair. Congruently, the tumor cells expressing high levels of variant-V can tolerate chemotherapeutic drug treatment better than the RAGE depleted cells. Our findings reveal a yet undisclosed role of the RAGE variant-V in the homology-directed DNA repair. This variant thus can be a potential target to be considered for future therapeutic approaches in advanced SSLC.