Reducing Chemotherapy-Induced DNA Damage via nAChR-Mediated Redox Reprograming—A New Mechanism for SCLC Chemoresistance Boosted by Nicotine

SIMPLE SUMMARY: Tobacco smoking is the dominant risk factor for lung cancer, particularly for small cell lung cancer (SCLC). Smoking is also associated with worse clinical outcomes of SCLC. For SCLC patients, platinum-based chemotherapy (cisplatin or carboplatin), in combination with etoposide, has been the first-line therapy for decades, even with the recent introduction of immunotherapy. One key limitation of such chemotherapy is the quick acquisition of drug resistance. Here, we found that nicotine and its main metabolite, cotinine, reduced the efficacy of chemotherapies to SCLC cells and accelerated drug resistance, which could contribute to poorer survival rates in SCLC patients who continue to smoke. ABSTRACT: Up to 60% of patients with small cell lung cancer (SCLC) continue to smoke, which is associated with worse clinical outcomes. Platinum-based chemotherapies, in combination with topoisomerase inhibitors, are first-line therapies for SCLC, with rapid chemoresistance as a major barrier. We provided evidence in this study that nicotine and its major metabolite, cotinine, at physiologically relevant concentrations, reduced the efficacy of platinum-based chemotherapies and facilitated chemoresistance in SCLC cells. Mechanistically, nicotine or cotinine reduced chemotherapy-induced DNA damage by modulating cellular redox processes, with nAChRs as the upstream targets. Surprisingly, cisplatin treatment alone also increased the levels of nAChRs in SCLC cells, which served as a self-defense mechanism against platinum-based therapies. These discoveries were confirmed in long-term in vitro and in vivo studies. Collectively, our results depicted a novel and clinically important mechanism of chemoresistance in SCLC treatment: nicotine exposure significantly compromises the efficacy of platinum-based chemotherapies in SCLC treatment by reducing therapy-induced DNA damage and accelerating chemoresistance acquisition. The results also emphasized the urgent need for tobacco cessation and the control of NRT use for SCLC management.