{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T18:20:19Z","timestamp":1770229219508,"version":"3.49.0"},"reference-count":45,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,11,29]],"date-time":"2025-11-29T00:00:00Z","timestamp":1764374400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2025,11,29]],"date-time":"2025-11-29T00:00:00Z","timestamp":1764374400000},"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":["Cancer Science"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>The current standard postoperative adjuvant therapy for patients with epidermal growth factor receptor (EGFR)\u2010mutated non\u2010small cell lung cancer (NSCLC) includes chemotherapy, including microtubule inhibitors prior to the administration of osimertinib, an EGFR\u2010tyrosine kinase inhibitor (TKI). However, multidrug resistance following treatment with microtubule inhibitors has been reported, and the optimal sequence of drug administration for EGFR\u2010mutated NSCLC remains undefined. In this study, we investigated whether prior treatment with microtubule inhibitors induces acquired cross\u2010resistance to osimertinib in EGFR\u2010mutated NSCLC cells in\u00a0vitro. To model acquired resistance, PC\u20109 cells were exposed to vinorelbine or paclitaxel for 18\u2009weeks\u2014approximating the clinical duration of four adjuvant chemotherapy cycles\u2014and subsequent drug sensitivity and signaling pathway alterations were assessed using cell viability assays, RNA sequencing, and immunoblotting. We found that two human NSCLC cell lines derived from PC\u20109 exhibited reduced sensitivity to osimertinib after 18\u2009weeks of in\u00a0vitro treatment with tubulin inhibitors: vinorelbine (PC\u20109\/VNR) and paclitaxel (PC\u20109\/PTX). Furthermore, PC\u20109\/VNR and PC\u20109\/PTX cells showed activation of FZD7 and calcium\/calmodulin\u2010dependent protein kinase II (CaMKII), along with increased sensitivity to the CaMKII inhibitor KN\u201093, which exerted additive or synergistic effects. These findings suggest that CaMKII plays a critical role in EGFR\u2010TKI resistance. This study underscores the importance of optimizing the timing of EGFR\u2010TKI administration in the therapeutic sequence for EGFR\u2010mutated NSCLC.<\/jats:p>","DOI":"10.1111\/cas.70274","type":"journal-article","created":{"date-parts":[[2025,11,29]],"date-time":"2025-11-29T10:10:52Z","timestamp":1764411052000},"page":"418-428","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Microtubule Inhibitors Induce Cross\u2010Resistance to Osimertinib Through\n                    <scp>CaMKII<\/scp>\n                    Activation in\n                    <scp>EGFR<\/scp>\n                    \u2010Mutated\n                    <scp>NSCLC<\/scp>"],"prefix":"10.1111","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5974-1741","authenticated-orcid":false,"given":"Kento","family":"Kono","sequence":"first","affiliation":[{"name":"Division of Medical Oncology and Respiratory Medicine, Department of Internal 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