Mechanism-guided management of therapeutic resistance in lung cancer through non-cross resistance and combination therapy

Therapeutic resistance remains a major obstacle to successful lung cancer treatment. This study investigated two complementary resistance-management strategies using in vitro models of small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC): addressing established resistance through treatment switching and delaying resistance emergence through combination therapy. In the SCLC model, a cisplatin-resistant N417 subline (N417/CDDP) was generated by prolonged exposure to cisplatin. Cell viability assays confirmed markedly reduced sensitivity to cisplatin in N417/CDDP cells compared with parental N417 cells. In contrast, paclitaxel retained substantial antiproliferative activity in both parental and cisplatin-resistant cells. Similar preservation of paclitaxel responsiveness was observed in cisplatin-exposed H82 cells, suggesting the potential utility of mechanistically distinct agents for further investigation in platinum-resistant settings. In the NSCLC model, EGFR-mutant PC-9 cells were continuously exposed to osimertinib or gefitinib alone or in combination with pemetrexed. Monotherapy resulted in relatively rapid resistance emergence, whereas combination treatment prolonged the time to resistance emergence. Both the osimertinib–pemetrexed and gefitinib–pemetrexed combinations delayed resistance emergence compared with EGFR tyrosine kinase inhibitor (EGFR-TKI) monotherapy under the experimental conditions used in this study. Collectively, these findings provide in vitro functional evidence supporting further investigation of two complementary approaches to resistance management: the use of mechanistically distinct agents after resistance has emerged and combination therapy to delay resistance emergence.