{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T01:22:14Z","timestamp":1792718534734,"version":"4.5.0"},"reference-count":70,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:00:00Z","timestamp":1784505600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>KRAS G12C, long considered an undruggable oncogenic driver, has become one of the most consequential therapeutic targets in non-small cell lung cancer (NSCLC). The discovery of a cryptic binding pocket accessible in the GDP-bound state enabled covalent inhibitors\u2014sotorasib and adagrasib\u2014that have received regulatory approval for previously treated KRAS G12C-mutant NSCLC, with sotorasib demonstrating PFS and OS superiority over docetaxel in CodeBreaK 200 and adagrasib showing meaningful intracranial activity and a progression-free survival benefit over docetaxel in KRYSTAL-12. Yet response durability is limited by on-target switch-II pocket mutations, upstream RTK and SHP2-mediated bypass signaling, downstream MAPK and PI3K-AKT reactivation, phenotypic plasticity, and adverse modulation by co-occurring STK11, KEAP1, and TP53 alterations. Next-generation covalent inhibitors (divarasib, glecirasib, olomorasib), tri-complex RAS(ON) inhibitors (RMC-6291), pan-KRAS agents, and rationally designed combinations with EGFR, SHP2, SOS1, and PD-1 inhibitors are repositioning KRAS-directed therapy toward earlier lines of treatment. This review integrates the structural, signaling, and clinical biology of KRAS G12C with contemporary trial and real-world evidence to examine the emerging case for first-line KRAS G12C inhibition in genomically defined subsets of NSCLC. First-line use nonetheless remains investigational; platinum-based chemoimmunotherapy remains the standard of care outside of clinical trials, and a frontline indication will require confirmation from randomized phase III trials.<\/jats:p>","DOI":"10.3390\/ijms27146455","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T16:19:27Z","timestamp":1784564367000},"page":"6455","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["KRAS G12C\u2013Targeted Therapy in Non-Small Cell Lung Cancer: From Resistant Salvage to Potential First-Line Backbone"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8909-5760","authenticated-orcid":false,"given":"Daniel","family":"Rosas","sequence":"first","affiliation":[{"name":"Memorial Cancer Institute, Hematology Oncology Fellowship, Hollywood, FL 33021, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8764-1382","authenticated-orcid":false,"given":"Priyanka","family":"Barad","sequence":"additional","affiliation":[{"name":"Harnett Health Internal Medicine Residency, Dunn, NC 28334, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jervon","family":"Wright","sequence":"additional","affiliation":[{"name":"Memorial Cancer Institute, Hematology Oncology Fellowship, Hollywood, FL 33021, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2669-5771","authenticated-orcid":false,"given":"Luis","family":"Raez","sequence":"additional","affiliation":[{"name":"Memorial Cancer Institute, Hematology Oncology Fellowship, Hollywood, FL 33021, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1038\/nature12796","article-title":"K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions","volume":"503","author":"Ostrem","year":"2013","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2371","DOI":"10.1056\/NEJMoa2103695","article-title":"Sotorasib for Lung Cancers with KRAS p.G12C Mutation","volume":"384","author":"Skoulidis","year":"2021","journal-title":"N. 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