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We demonstrate that the RAS(ON) inhibitor doublet induces profound and sustained tumor regressions and overcomes the increased RAS pathway oncogenic flux that underlies resistance to inactive state\u2013selective KRASG12C inhibitors in NSCLC. Additionally, in immune-competent preclinical models, the RAS(ON) inhibitor doublet enhances tumor immune recognition by boosting antigen presentation and remodeling the suppressive tumor microenvironment, thus promoting immune-dependent complete regressions and sensitization of an immunorefractory model to checkpoint blockade. Collectively, these findings provide a preclinical rationale for the evaluation of a targeted RAS(ON) inhibitor doublet therapy regimen in combination with immune checkpoint blockade (ICB) in patients with KRASG12C-mutant NSCLC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>The combination of a RAS(ON) G12C-selective and RAS(ON) multi-selective inhibitor mitigates clinical resistance mechanisms to KRASG12C(OFF) inhibitors and enhances tumor immune recognition, overcoming ICB resistance. These preclinical findings highlight the potential for a RAS(ON) targeted therapy regimen in combination with anti\u2013PD-(L)1 in patients with KRASG12C-mutant NSCLC.<\/jats:p>\n                    <jats:p>See related commentary by Molina-Arcas and Downward, p. 1044<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-25-1616","type":"journal-article","created":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T14:32:36Z","timestamp":1770820356000},"page":"1152-1175","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Abrogation of Oncogenic RAS Signaling by a RAS(ON) Inhibitor Doublet Primes Immune-Refractory\n                    <i>KRAS<\/i>\n                    <i>G12C<\/i>\n                    -Mutant NSCLC for Immune Checkpoint Blockade"],"prefix":"10.1158","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4584-3891","authenticated-orcid":false,"given":"Xing","family":"Wei","sequence":"first","affiliation":[{"name":"1Revolution Medicines, Inc., Redwood City, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0449-2690","authenticated-orcid":false,"given":"Cristina","family":"Blaj","sequence":"additional","affiliation":[{"name":"1Revolution Medicines, Inc., Redwood City, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6761-4520","authenticated-orcid":false,"given":"M.","family":"Ali Al-Radhawi","sequence":"additional","affiliation":[{"name":"1Revolution Medicines, Inc., Redwood City, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4395-1364","authenticated-orcid":false,"given":"Lick 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