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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\u2013shell dendrimers, using NSCLC cell lines harboring different EGFR and KRAS profiles. Cells were treated with PURE\n                    <jats:sub>G4<\/jats:sub>\n                    -OEI\n                    <jats:sub>48<\/jats:sub>\n                    and PURE\n                    <jats:sub>G4<\/jats:sub>\n                    -OCEI\n                    <jats:sub>24<\/jats:sub>\n                    dendrimers, which showed heterogeneous responses. In PC-9\n                    <jats:sup>\n                      <jats:italic>EGFREx19Del<\/jats:italic>\n                    <\/jats:sup>\n                    cells, PURE\n                    <jats:sub>G4<\/jats:sub>\n                    -OEI\n                    <jats:sub>48<\/jats:sub>\n                    induced elevated p-ERK\/ERK ratios, indicating activation of the ERK-MAPK pathway and resistance. Notably, the EGFR\n                    <jats:sup>Ex19Del<\/jats:sup>\n                    mutation contributed to this resistance. To overcome this effect, a synergistic strategy combining PURE\n                    <jats:sub>G4<\/jats:sub>\n                    -OEI\n                    <jats:sub>48<\/jats:sub>\n                    and PURE\n                    <jats:sub>G4<\/jats:sub>\n                    -OCEI\n                    <jats:sub>24<\/jats:sub>\n                    with the tyrosine kinase inhibitor (TKI) gefitinib was explored. This combination sensitized PC-9 cells, reducing ERK activation and enhancing cell death.\n                    <jats:italic>Ex vivo<\/jats:italic>\n                    chick chorioallantoic membrane (CAM) assays confirmed that EGFR\n                    <jats:sup>Ex19Del<\/jats:sup>\n                    drives resistance to PURE\n                    <jats:sub>G4<\/jats:sub>\n                    -OEI\n                    <jats:sub>48<\/jats:sub>\n                    , 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 EGFR\n                    <jats:sup>Ex19Del<\/jats:sup>\n                    -driven resistance. Overall, these findings highlight the translational potential of integrating membrane-targeted nanotherapeutics with EGFR-directed therapies to improve outcomes in NSCLC patients.\n                  <\/jats:p>","DOI":"10.1007\/s12672-026-04934-0","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T12:53:19Z","timestamp":1776430399000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Polycationic dendrimers synergizes with gefitinib to overcome EGFREx19Del-driven resistance in non-small-cell lung cancer"],"prefix":"10.1007","volume":"17","author":[{"given":"Adriana","family":"Cruz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruna","family":"Abreu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cindy","family":"Mendes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Lemos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catarina","family":"Freitas-Dias","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"Gomes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruna","family":"Sousa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filipe","family":"Gon\u00e7alves","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 S.","family":"Ramalho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duarte C.","family":"Barral","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vasco D. 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According to European Directive 2010\/63\/EU on the protection of animals used for scientific purposes, the chick embryo is not considered a protected animal until day 17 of development, since pain perception and nociception are not established before this stage (doi:\n                      \n                      ). Consequently, experiments conducted up to embryonic day 17 do not require ethics committee approval and there is no standardized maximum tumor size for these experiments. The project was approved by NOVA Medical School Ethical Committee (Ref: 75\/2020\/CEFCM).\n                      Human samples\n                      : The study was approved by the Ethics Committee of Instituto Portugu\u00eas de Oncologia de Lisboa Francisco Gentil (IPO Lisboa) (reference UIC\/1349). The research was conducted in accordance with the ethical standards of the approving committee and applicable institutional regulations (\n                      \n                      ). Samples from healthy blood donors were analyzed anonymously. Informed consent to participate was obtained from all healthy blood donors included in the study, as approved by the\n                      Instituto Portugu\u00eas de Oncologia de Lisboa\n                      ,\n                      Francisco Gentil\n                      (IPOLFG)-Ethical committee (UIC-1349).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"811"}}