m6A regulators as predictive biomarkers for chemotherapy benefit and potential therapeutic targets for overcoming chemotherapy resistance in small-cell lung cancer

Small-cell lung cancer (SCLC) is a devastating subtype of lung cancer with few therapeutic options. Despite the advent of immunotherapy, platinum-based chemotherapy is still the irreplaceable first-line therapy for SCLCs. However, drug resistance will invariably occur in most patients and the outcomes are heterogeneous. Therefore, clinically feasible classification strategies and potential therapeutic targets for overcoming chemotherapy resistance are urgently needed. N⁶-methyladenosine (m⁶A) is a novel epigenetic decisive factor that is involved in tumor progression and drug resistance. However, almost nothing is known about m⁶A modification in SCLC. Here, we assessed 200 SCLC samples from patients who underwent chemotherapy from three different cohorts, including a validation cohort containing 71 cases with qPCR data and an independent cohort containing 79 cases with immunohistochemistry data (quantified as H-score). We systematically characterized the predictive landscape of m⁶A regulators in SCLC patients following with chemotherapy. Using the LASSO Cox model, we built a seven-regulator-based (ZCCHC4, IGF2BP3, ALKBH5, YTHDF3, METTL5, G3BP1, and RBMX) chemotherapy benefit predictive classifier (m⁶A score) and subsequently validated the classifier in two other cohorts. Time-dependent ROC and C-index analyses showed that the m⁶A score to possessed superior predictive power for chemotherapy benefit in comparison with other clinicopathological parameters. A multicohort multivariate analysis revealed that the m⁶A score is an independent factor that affects survival benefit across multiple cohorts. Our in vitro experimental results revealed that three regulators-ZCCHC4, G3BP1, and RBMX-may serve as promising novel therapeutic targets for overcoming chemoresistance in SCLCs. Our results, for the first time, demonstrate the predictive significance of m⁶A regulators for chemotherapy benefit, as well as their potential as therapeutic targets for overcoming chemotherapy resistance in SCLC patients. The m⁶A score was found to be a reliable prognostic tool that may help guide chemotherapy decisions for patients with SCLC.