{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T07:33:07Z","timestamp":1793259187435,"version":"4.5.0"},"reference-count":39,"publisher":"Wiley","issue":"20","license":[{"start":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T00:00:00Z","timestamp":1792713600000},"content-version":"vor","delay-in-days":22,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Thoracic Cancer"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>Pemetrexed, a standard antifolate chemotherapy for non\u2010squamous non\u2010small cell lung cancer (NSCLC), is often limited by acquired resistance. We investigated whether SRC kinase mediates pemetrexed resistance and whether SRC inhibition can suppress survival signaling in pemetrexed\u2010resistant NSCLC cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Pemetrexed\u2010resistant cell lines (PC9 R, NCI\u2010H460 R, and NCI\u2010H3122 R) were generated through chronic pemetrexed exposure. Protein phosphorylation profiling and Western blotting identified key signaling alterations. SRC was abrogated using transient and doxycycline\u2010inducible CRISPR\/Cas9 systems, and reciprocal siRNA knockdown of SRC and thymidylate synthase (TS) was performed. Three SRC inhibitors\u2014dasatinib, bosutinib, and saracatinib\u2014were assessed using cell viability, colony formation, apoptosis, and cell cycle assays.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>All pemetrexed\u2010resistant cell lines demonstrated elevated phosphorylated SRC (p\u2010SRC Y416) and enhanced downstream signaling. SRC knockout reduced p\u2010SRC Y416, p\u2010STAT3, and p\u2010FAK, while increasing markers of DNA damage (\u03b3\u2010H2AX) and apoptosis (cleaved caspase\u20103), impairing cell viability and clonogenicity. SRC knockdown reduced TS expression in two resistant models, whereas TS knockdown did not suppress p\u2010SRC Y416. Among SRC inhibitors, dasatinib showed the most potent, dose\u2010dependent suppression of SRC signaling. Dasatinib also induced G0\/G1 arrest, DNA damage, and apoptosis, thereby reducing colony formation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>SRC activation is a critical mechanism of acquired pemetrexed resistance in NSCLC and may contribute to resistance through TS\u2010associated survival signaling. SRC inhibition, particularly with dasatinib, disrupts pro\u2010survival pathways and promotes DNA damage\u2010mediated cell death in pemetrexed\u2010resistant cells. These findings support further investigation of SRC inhibitors, alone or with pemetrexed, as a biomarker\u2010guided therapeutic strategy for SRC\u2010activated pemetrexed\u2010resistant NSCLC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/1759-7714.70406","type":"journal-article","created":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T00:31:12Z","timestamp":1792801872000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>SRC<\/scp>\n                    Activation Drives Acquired Pemetrexed Resistance in Non\u2010Small Cell Lung Cancer and Is Targetable by Dasatinib"],"prefix":"10.1111","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9992-6273","authenticated-orcid":false,"given":"Jeongmin","family":"Seo","sequence":"first","affiliation":[{"name":"Department of Internal Medicine Seoul National University Bundang Hospital, Seoul National University College of Medicine  Seongnam Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kui\u2010Jin","family":"Kim","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute Seoul National University Bundang Hospital  Seongnam Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2292-906X","authenticated-orcid":false,"given":"Se Hyun","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Seoul National University Bundang Hospital, Seoul National University College of Medicine  Seongnam Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji Hea","family":"Sung","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Seoul National University Bundang Hospital, Seoul National University College of Medicine  Seongnam Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2413-5287","authenticated-orcid":false,"given":"Sung\u2010Hyun","family":"Hwang","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute Seoul National University Bundang Hospital  Seongnam Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1696-8214","authenticated-orcid":false,"given":"Woochan","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Seoul National University Bundang Hospital, Seoul National University College of Medicine  Seongnam Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6491-2277","authenticated-orcid":false,"given":"Minsu","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Seoul National University Bundang Hospital, Seoul National University College of Medicine  Seongnam Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun Hee","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Seoul National University Bundang Hospital, Seoul National University College of Medicine  Seongnam Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8529-0232","authenticated-orcid":false,"given":"Sang\u2010A","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Seoul National University Bundang Hospital, Seoul National University College of Medicine  Seongnam Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koung Jin","family":"Suh","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Seoul National University Bundang Hospital, Seoul National University College of Medicine  Seongnam Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5835-7219","authenticated-orcid":false,"given":"Ji Yun","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Seoul National University Bundang Hospital, Seoul National University College of Medicine  Seongnam Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6426-9074","authenticated-orcid":false,"given":"Ji\u2010Won","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Seoul National University Bundang Hospital, Seoul National University College of Medicine  Seongnam Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9402-6372","authenticated-orcid":false,"given":"Jeong\u2010Ok","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Internal 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