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The MUC1-encoded oncogenic M1C protein is necessary for self-renewal of NSCLC KRAS mutant cells. We report that treatment of NSCLC KRAS G12C cells with sotorasib induces M1C expression by a STAT1-dependent pathway. In turn, M1C drives the sotorasib resistant phenotype by NF-\u03baB-mediated induction of the epithelial-mesenchymal transition (EMT) and a mucinous gene program. Targeting M1C\u2192NF-\u03baB signaling (i) suppresses EMT and mucin genes, and (ii) reverses sotorasib resistance. Of translational relevance, treatment with a M1C antibody-drug conjugate (ADC) is effective against two sotorasib-resistant NSCLC KRAS G12C cell lines and two patient-derived tumor xenograft models. Analysis of patients with NSCLC KRAS G12C tumors treated with sotorasib\/adagrasib and overexpressing MUC1 associates with decreases in overall survival. These findings identify M1C as a key effector of sotorasib resistance and as a target for treatment of patients with refractory NSCLC KRAS G12C mutant tumors.<\/jats:p>","DOI":"10.1038\/s41388-026-03934-2","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T12:51:31Z","timestamp":1785934291000},"page":"4088-4100","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["M1C is a druggable target for NSCLC KRAS G12C mutant tumors resistant to KRAS inhibitors"],"prefix":"10.1038","volume":"45","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"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3771-7940","authenticated-orcid":false,"given":"Hiroki","family":"Ozawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keisuke","family":"Shigeta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mai","family":"Onishi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kentaro","family":"Nonaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takefumi","family":"Komiya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroki","family":"Komatsuda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoyoshi","family":"Takenaka","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"}]},{"given":"Chendi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiehui","family":"Deng","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\/0000-0001-6323-235X","authenticated-orcid":false,"given":"Kwok K.","family":"Wong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1120-8176","authenticated-orcid":false,"given":"Mark D.","family":"Long","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":[[2026,8,5]]},"reference":[{"key":"3934_CR1","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1056\/NEJMoa2204619","volume":"387","author":"PA Janne","year":"2022","unstructured":"Janne PA, Riely GJ, Gadgeel SM, Heist RS, Ou SI, Pacheco JM, et al. 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JCI Insight. 2025;10:e190924.","journal-title":"JCI Insight"}],"container-title":["Oncogene"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41388-026-03934-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41388-026-03934-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41388-026-03934-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T22:02:22Z","timestamp":1789509742000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41388-026-03934-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,5]]},"references-count":47,"journal-issue":{"issue":"38","published-print":{"date-parts":[[2026,10,7]]}},"alternative-id":["3934"],"URL":"https:\/\/doi.org\/10.1038\/s41388-026-03934-2","relation":{},"ISSN":["0950-9232","1476-5594"],"issn-type":[{"value":"0950-9232","type":"print"},{"value":"1476-5594","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,5]]},"assertion":[{"value":"5 March 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 July 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 July 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 August 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"All methods were performed in accordance with the relevant institutional guidelines and regulations. Studies performed on live vertebrates were conducted in accordance with ethical regulations required for approval by the Dana-Farber Cancer Institute Animal Care and Use Committee (IACUC) under protocol 03-029. Analysis of the KRYSTAL-1 trial and CARIS CODEai databases was performed using publicly available deidentified information which did not require informed consent from the patients. No identifiable images from human research participants were included in the present work.","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"D.K. has equity interests in Genus Oncology. The authors declare no competing interests.","order":2,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}]}}