Polycationic dendrimers synergizes with gefitinib to overcome EGFREx19Del-driven resistance in non-small-cell lung cancer.

Lung cancer is a heterogeneous disease and the leading cause of cancer-related deaths worldwide. The aggressiveness of non-small-cell lung cancer (NSCLC) is often associated with oncogenic activation of the mitogen-activated protein kinase (MAPK) pathway. Among the most prevalent mutations in NSCLC, epidermal growth factor receptor 1 (EGFR) and Kirsten rat sarcoma (KRAS) alterations play a key role in cancer progression and patient survival. In this study, we investigated the influence of EGFR and KRAS mutational status on the response to polycationic core-shell dendrimers, using NSCLC cell lines harboring different EGFR and KRAS profiles. Cells were treated with PUREG4-OEI48 and PUREG4-OCEI24 dendrimers, which showed heterogeneous responses. In PC-9EGFREx19Del cells, PUREG4-OEI48 induced elevated p-ERK/ERK ratios, indicating activation of the ERK-MAPK pathway and resistance. Notably, the EGFREx19Del mutation contributed to this resistance. To overcome this effect, a synergistic strategy combining PUREG4-OEI48 and PUREG4-OCEI24 with the tyrosine kinase inhibitor (TKI) gefitinib was explored. This combination sensitized PC-9 cells, reducing ERK activation and enhancing cell death. Ex vivo chick chorioallantoic membrane (CAM) assays confirmed that EGFREx19Del drives resistance to PUREG4-OEI48, whereas co-treatment with gefitinib improves efficacy. The use of complex dendrimer systems allows precise modulation of membrane-targeted interactions and intracellular signaling, providing mechanistic insights into overcoming EGFREx19Del-driven resistance. Overall, these findings highlight the translational potential of integrating membrane-targeted nanotherapeutics with EGFR-directed therapies to improve outcomes in NSCLC patients.