Abstract

Chemotherapies based on platinum have been the standard first-line treatment for patients with small-cell lung cancer(SCLC) in the past years. However, the progression of patients occurs mostly due to rapid development of resistance to chemotherapy. In addition, the mechanisms involved in development of cisplatin-resistance in SCLC remain undetermined. Here, we analyzed whole-exome sequencing(WES) datasets from Genomics of Drug Sensitivity in Cancer(GDSC, N=55) and WES data and overall survival(OS) from a published cohort(N=101) to search for cisplatin-resistant target genes and genes associated with poor prognosis. We use our cohort(NCT03162705) as the validation set. We applied single sample gene set enrichment analysis(ssGSEA) to explore the potential molecular mechanisms of cisplatin-resistance. DNAH10 mutations in SCLC was significantly associated with cisplatin-resistance(P=0.0350), poor OS(HR:3.445;P=0.00035) and worse progression-free survival (PFS)(P=0.0142). ssGSEA showed that the negative regulation of FGFR, the SPRY regulation of FGF, and the positive regulation of noncanonical WNT and PI3K/AKT/IKK signaling pathways are differentially up- or downregulated in DNAH10-mutated cell lines. A higher TMB was observed in DNAH10-mutated cell lines. Taken together, DNAH10 mutations may have a potential value in prediction of cisplatin resistance and poor survival in SCLC. Moreover, DNAH10 mutations may have a positive correlation with high TMB in SCLC.