{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T07:48:37Z","timestamp":1794037717049,"version":"4.8.0"},"reference-count":35,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"835","funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01CA276058"],"award-info":[{"award-number":["R01CA276058"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NIH 5P50CA070907"],"award-info":[{"award-number":["NIH 5P50CA070907"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000048","name":"American Cancer Society","doi-asserted-by":"publisher","award":["RSG-22-051-01-IBCD"],"award-info":[{"award-number":["RSG-22-051-01-IBCD"]}],"id":[{"id":"10.13039\/100000048","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA289500"],"award-info":[{"award-number":["R01CA289500"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004917","name":"Cancer Prevention and Research Institute of Texas","doi-asserted-by":"publisher","award":["RR160080"],"award-info":[{"award-number":["RR160080"]}],"id":[{"id":"10.13039\/100004917","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100019937","name":"William Guy Forbeck Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100019937","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2026,2,4]]},"abstract":"<jats:p>\n                    The development of allele-specific KRAS inhibitors underscores the importance of understanding the distinct tumor biology associated with common\n                    <jats:italic toggle=\"yes\">KRAS<\/jats:italic>\n                    mutations, G12D and G12C, in genetically engineered mouse models (GEMMs) of non\u2013small cell lung cancer (NSCLC) and patient samples. Lung tumors driven by the most common\n                    <jats:italic toggle=\"yes\">KRAS<\/jats:italic>\n                    mutation, G12C, show delayed onset and slower progression compared with those driven by KRAS G12D in patients and mice. G12C tumors display lower proliferation and increased immune cell engagement, the latter of which is consistent with observations in patient tumors. Allele-specific KRAS G12C\/D inhibitors effectively suppress the growth of respective autochthonous lung tumors. However, G12D-driven tumors relapse more rapidly than G12C-driven tumors in autochthonous models, reflecting greater intrinsic aggressiveness. Given this aggressive clinical behavior, we focused on elucidating the mechanism of action and strategies to potentiate KRAS\n                    <jats:sup>G12D<\/jats:sup>\n                    inhibition in nonimmunogenic and immunogenic lung cancer models. G12D inhibition enhances tumor antigen presentation, activates T cells, and enables antigen-specific cytotoxicity, leading to efficacy with immune checkpoint blockade combination. This combination induces durable immune memory in immunogenic models but not in nonimmunogenic settings. Our findings underscore key differences between KRAS G12D and G12C mutations in shaping lung cancer biology, reveal distinct resistance dynamics under long-term targeted therapy, and uncover immune-mediated mechanisms specific to KRAS\n                    <jats:sup>G12D<\/jats:sup>\n                    inhibition with direct clinical and translational relevance.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adq6647","type":"journal-article","created":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T18:58:12Z","timestamp":1770231492000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":8,"title":["Kras G12C\u2013 and G12D\u2013driven lung cancers differ in oncogenic potency, immunogenicity, and relapse after Kras inhibition in mouse models"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2369-6288","authenticated-orcid":true,"given":"Hai-Cheng","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA."},{"name":"Harold C. Simmons Comprehensive Cancer Center, Dallas, TX 75390, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9835-6889","authenticated-orcid":true,"given":"Qing","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA."},{"name":"Harold C. Simmons Comprehensive Cancer Center, Dallas, TX 75390, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Guo","sequence":"additional","affiliation":[{"name":"Quantitative Biomedical Research Center, Department of Population &amp; Data Sciences, Dallas, TX 75390, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Gorria","sequence":"additional","affiliation":[{"name":"Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Pecci","sequence":"additional","affiliation":[{"name":"Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2836-6755","authenticated-orcid":true,"given":"Daniella","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA."},{"name":"Harold C. Simmons Comprehensive Cancer Center, Dallas, TX 75390, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott","family":"Rodig","sequence":"additional","affiliation":[{"name":"Department of Pathology, Brigham and Women\u2019s Hospital, Boston, MA 02115, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis","family":"De Las Casas","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8443-7116","authenticated-orcid":true,"given":"Jill","family":"Hallin","sequence":"additional","affiliation":[{"name":"Mirati Pharmaceuticals (a Bristol Myers Squibb company), San Diego, CA 92121, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James G.","family":"Christensen","sequence":"additional","affiliation":[{"name":"Mirati Pharmaceuticals (a Bristol Myers Squibb company), San Diego, CA 92121, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0928-5244","authenticated-orcid":true,"given":"Mark M.","family":"Awad","sequence":"additional","affiliation":[{"name":"Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5815-4457","authenticated-orcid":true,"given":"Lin","family":"Xu","sequence":"additional","affiliation":[{"name":"Harold C. Simmons Comprehensive Cancer Center, Dallas, TX 75390, USA."},{"name":"Quantitative Biomedical Research Center, Department of Population &amp; Data Sciences, Dallas, TX 75390, USA."},{"name":"Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX 75390, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Biagio","family":"Ricciuti","sequence":"additional","affiliation":[{"name":"Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4149-2529","authenticated-orcid":true,"given":"Esra A.","family":"Akbay","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA."},{"name":"Harold C. 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