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Clinical and epidemiological data suggest association between specific KRAS alleles, therapeutic responses, and patient outcomes, however, direct experimental validation of these relationships has been limited. In this study, we investigate the differential impacts of three most common K-Ras G12 mutants (K-Ras\n                    <jats:sup>G12C<\/jats:sup>\n                    , K-Ras\n                    <jats:sup>G12D<\/jats:sup>\n                    , and K-Ras\n                    <jats:sup>G12V<\/jats:sup>\n                    ) in the colon using in vivo models. Although tumors harboring different Gly12 mutants exhibited no obvious histological differences, their effects on survival outcomes and therapeutic responses displayed pronounced allele specific differences. Transcriptomic analyses revealed an allele-agnostic signature enriched for gene sets associated with MAPK signaling, receptor tyrosine kinase pathways, and immune-modulating pathways, relative to K-Ras WT tumors. In contrast, the allele-specific signature revealed marked enrichment of Notch and Wnt\/\u03b2-catenin signaling pathways in K-Ras\n                    <jats:sup>G12C<\/jats:sup>\n                    tumors. Pharmacological inhibition of these pathways, in combination with a K-Ras\n                    <jats:sup>G12C<\/jats:sup>\n                    inhibitor, led to either addictive or synergistic reduction in tumor cell viability, in an allele-specific manner. These findings highlight the distinct biological consequences of individual K-Ras G12 mutations in colonic tumorigenesis and underscore therapeutic relevance of allele-specific signaling dependencies, offering a foundation for the development of effective, allele-informed therapeutic strategies for K-Ras mutant cancers.\n                  <\/jats:p>","DOI":"10.1038\/s41388-026-03771-3","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T11:01:09Z","timestamp":1775818869000},"page":"1828-1839","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The impact of K-Ras Gly12 mutants on homeostasis and tumorigenesis in the colonic epithelium"],"prefix":"10.1038","volume":"45","author":[{"given":"Moon Hee","family":"Yang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shikha","family":"Sheth","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bing","family":"Shui","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isabella N.","family":"Grabski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samuel Seongmin","family":"Park","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0988-1823","authenticated-orcid":false,"given":"Ana","family":"Cobo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rafael","family":"Irizarri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9068-8942","authenticated-orcid":false,"given":"John V.","family":"Heymach","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7048-1418","authenticated-orcid":false,"given":"Lukas E.","family":"Dow","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1922-4509","authenticated-orcid":false,"given":"Kevin M.","family":"Haigis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,4,10]]},"reference":[{"key":"3771_CR1","doi-asserted-by":"publisher","first-page":"2969","DOI":"10.1158\/0008-5472.CAN-19-3682","volume":"80","author":"IA Prior","year":"2020","unstructured":"Prior IA, Hood FE, Hartley JL. 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Sci Rep. 2020;10:10149.","journal-title":"Sci Rep"}],"container-title":["Oncogene"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41388-026-03771-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41388-026-03771-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41388-026-03771-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T22:02:29Z","timestamp":1777932149000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41388-026-03771-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,10]]},"references-count":50,"journal-issue":{"issue":"19","published-print":{"date-parts":[[2026,5,26]]}},"alternative-id":["3771"],"URL":"https:\/\/doi.org\/10.1038\/s41388-026-03771-3","relation":{},"ISSN":["0950-9232","1476-5594"],"issn-type":[{"value":"0950-9232","type":"print"},{"value":"1476-5594","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,10]]},"assertion":[{"value":"31 July 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 January 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 March 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 April 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"K.M.H. received research funding from Revolution Medicines.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"and consent to participate: All methods were performed in accordance with the relevant guidelines and regulations. All procedures involving animals were approved by the Institutional Animal Care and Use Committee of Beth Israel Deaconess Medical Center (protocol number: 21-029) and conducted in accordance with institutional guidelines. No human samples or identifiable images are included in this study.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}}]}}