{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T02:45:59Z","timestamp":1773715559633,"version":"3.50.1"},"reference-count":48,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T00:00:00Z","timestamp":1756944000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Japan Society for the Promotion of Science","award":["22K07291"],"award-info":[{"award-number":["22K07291"]}]},{"name":"Japan Society for the Promotion of Science","award":["23K15569"],"award-info":[{"award-number":["23K15569"]}]},{"name":"Japan Society for the Promotion of Science","award":["22K08986"],"award-info":[{"award-number":["22K08986"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Afatinib and osimertinib are current treatment options for non-small cell lung cancer (NSCLC) patients with uncommon epidermal growth factor receptor (EGFR) mutations, although their efficacy is limited. To explore potentially effective drugs for these patients, we evaluated the efficacy of conventional EGFR tyrosine kinase inhibitors (TKIs) and novel third-generation (3G) TKIs using in vitro models. Ba\/F3 cells transformed with each of the five most frequent uncommon EGFR mutations, Del18 (delE709_T710insD), E709K, G719A, S768I, and L861Q, were used. The growth inhibitory effects of five novel 3G-TKIs, almonertinib, lazertinib, furmonertinib, rezivertinib, and befotertinib, in addition to currently available TKIs, were evaluated. We also explored for secondary resistant mutations to afatinib or osimertinib and TKIs that can overcome these resistances. Afatinib was active against all uncommon EGFR mutations tested. The 3G-TKIs were all active against the L861Q mutation and were inactive against the S768I mutation. Furmonertinib and befotertinib showed efficacy against exon 18 mutations (Del18, E709K, and G719A). In the acquired resistance models to afatinib or osimertinib, we found T790M or a novel T725M secondary mutation, respectively, both of which could be overcome by lazertinib. However, some afatinib-resistant cells acquired V769L\/M secondary mutations that were refractory to all EGFR-TKIs tested. In conclusion, afatinib exhibited broad activity and some 3G-TKIs showed promising efficacy in the front-line setting. Lazertinib is a potential second-line option after acquisition of resistance to afatinib or osimertinib.<\/jats:p>","DOI":"10.3390\/cells14171386","type":"journal-article","created":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T15:31:21Z","timestamp":1756999881000},"page":"1386","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Efficacy of Conventional and Novel Tyrosine Kinase Inhibitors for Uncommon EGFR Mutations\u2014An In Vitro Study"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-9384-5577","authenticated-orcid":false,"given":"Hana","family":"Oiki","sequence":"first","affiliation":[{"name":"Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0842-8832","authenticated-orcid":false,"given":"Kenichi","family":"Suda","sequence":"additional","affiliation":[{"name":"Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Japan"},{"name":"Division of Thoracic Surgery, Izumi City General Hospital, Izumi 594-0073, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1689-9447","authenticated-orcid":false,"given":"Akira","family":"Hamada","sequence":"additional","affiliation":[{"name":"Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshio","family":"Fujino","sequence":"additional","affiliation":[{"name":"Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Japan"},{"name":"Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA"},{"name":"Department of Medicine, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keiko","family":"Obata","sequence":"additional","affiliation":[{"name":"Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshihisa","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo 104-0045, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuko","family":"Sakai","sequence":"additional","affiliation":[{"name":"Department of Genome Biology, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3522-834X","authenticated-orcid":false,"given":"Shota","family":"Fukuda","sequence":"additional","affiliation":[{"name":"Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9159-8743","authenticated-orcid":false,"given":"Shuta","family":"Ohara","sequence":"additional","affiliation":[{"name":"Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masaoki","family":"Ito","sequence":"additional","affiliation":[{"name":"Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8532-7915","authenticated-orcid":false,"given":"Junichi","family":"Soh","sequence":"additional","affiliation":[{"name":"Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Japan"},{"name":"Department of Thoracic Surgery, Graduate School of Medicine, Osaka Metropolitan University, Osaka 558-8585, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8275-0846","authenticated-orcid":false,"given":"Kazuto","family":"Nishio","sequence":"additional","affiliation":[{"name":"Department of Genome Biology, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tetsuya","family":"Mitsudomi","sequence":"additional","affiliation":[{"name":"Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Japan"},{"name":"Division of Thoracic Surgery, Izumi City General Hospital, Izumi 594-0073, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8836-1027","authenticated-orcid":false,"given":"Yasuhiro","family":"Tsutani","sequence":"additional","affiliation":[{"name":"Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1093\/jnci\/dji055","article-title":"Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers","volume":"97","author":"Shigematsu","year":"2005","journal-title":"J. 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