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We report that the oncogenic MUC1-C\/M1C protein confers resistance to osimertinib by regulating the STAT1 and interferon (IFN) type I\/II pathways. Studies of osimertinib-resistant NSCLC cell lines selected for growth in the absence of drug demonstrate dependence on MUC1-C and the STAT1 pathway for memory of the refractory phenotype. This inflammatory memory of TKI resistance is mediated through activation of the\n                    <jats:italic>MUC1<\/jats:italic>\n                    gene at (i) a proximal enhancer-like signature 1 (pELS-1) by MUC1-C and STAT1 and (ii) a pELS-2 by MUC1-C, JUN\/AP-1, and PBAF. Our results further reveal that the MUC1-C-driven STAT1 inflammatory response promotes resistance of patient-derived (i) EGFR mutant NSCLC cells with\n                    <jats:italic>MET<\/jats:italic>\n                    amplification to the combination of osimertinib+MET TKIs, and (ii) EGFR(T790M\/C797S) NSCLC cells to the 4th generation EGFR TKI TQB3804. Of clinical significance, we report that NSCLC cells dependent on MUC1-C for TKI resistance are druggable with an antibody-drug conjugate (M1C ADC) in vitro and in a PDX tumor model. These findings demonstrate that MUC1-C (i) is essential for TKI resistance of NSCLC cells by driving an inflammatory memory response and (ii) is a target for M1C ADC treatment of TKI-refractory NSCLCs.\n                  <\/jats:p>","DOI":"10.1038\/s41392-025-02482-7","type":"journal-article","created":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T23:01:43Z","timestamp":1764284503000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["MUCIN 1 confers inflammatory memory of tyrosine kinase inhibitor resistance in non-small cell lung cancer"],"prefix":"10.1038","volume":"10","author":[{"given":"Shinkichi","family":"Takamori","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoki","family":"Haratake","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atrayee","family":"Bhattacharya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chie","family":"Kikutake","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroki","family":"Ozawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keisuke","family":"Shigeta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2443-6995","authenticated-orcid":false,"given":"Ayako","family":"Nakashoji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideko","family":"Isozaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mototsugu","family":"Shimokawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikita","family":"Suyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asato","family":"Hashinokuchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuki","family":"Takada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gouji","family":"Toyokawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuichi","family":"Yamada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoyoshi","family":"Takenaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenichi","family":"Taguchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masafumi","family":"Yamaguchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4497-1816","authenticated-orcid":false,"given":"Tomoharu","family":"Yoshizumi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6127-318X","authenticated-orcid":false,"given":"Aaron N.","family":"Hata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5743-8888","authenticated-orcid":false,"given":"Donald","family":"Kufe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,28]]},"reference":[{"key":"2482_CR1","doi-asserted-by":"publisher","first-page":"1046","DOI":"10.1158\/2159-8290.CD-14-0337","volume":"4","author":"DA Cross","year":"2014","unstructured":"Cross, D. 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