{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T02:41:32Z","timestamp":1788316892103,"version":"build-2803163510"},"reference-count":37,"publisher":"Harborside Press, LLC","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:p>Colorectal cancer (CRC) is a heterogeneous group of diseases comprising several molecular subtypes. Comprehensive DNA sequencing is now standard practice to identify these subtype. Until recently, <jats:italic>KRAS<\/jats:italic> mutation status in metastatic CRC was primarily used as a biomarker to predict resistance to EGFR inhibition. However, with up to 40% of CRC cases harboring <jats:italic>KRAS<\/jats:italic> mutations, therapeutic targeting of RAS has been an area of great need. The development of KRAS<jats:sup>G12C<\/jats:sup> inhibitors has led to the FDA approval of drugs for treating non\u2013small cell lung cancer. Recently, these and other newly developed inhibitors have been investigated as monotherapies and in combination for metastatic <jats:italic>KRAS<\/jats:italic><jats:sup>G12C<\/jats:sup>-mutant CRC. This review examines the development of these inhibitors and highlights data supporting the inclusion of sotorasib and adagrasib, in combination with either panitumumab or cetuximab, in the NCCN Guidelines for CRC for the treatment of refractory metastatic disease.<\/jats:p>","DOI":"10.6004\/jnccn.2024.7067","type":"journal-article","created":{"date-parts":[[2025,1,3]],"date-time":"2025-01-03T15:52:23Z","timestamp":1735919543000},"source":"Crossref","is-referenced-by-count":10,"title":["Development of KRAS Inhibitors and Their Role for Metastatic Colorectal Cancer"],"prefix":"10.6004","volume":"23","author":[{"given":"Dustin A.","family":"Deming","sequence":"first","affiliation":[{"name":"Division of Hematology, Medical Oncology, and Palliative Care, Department of Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI"},{"name":"University of Wisconsin Carbone Cancer Center, Madison, WI"},{"name":"Department of Oncology, McArdle Laboratory for Cancer Research, Madison, WI"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4047","reference":[{"key":"B1","series-title":"CA Cancer J Clin","first-page":"12","article-title":"Cancer statistics, 2024","volume":"74","author":"Siegel RL","year":"2024","unstructured":"Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin 2024;74:12\u201349."},{"key":"B2","article-title":"NCCN Clinical Practice Guidelines in Oncology: Colon Cancer. Version 5.2024","author":"Benson AB III","unstructured":"Benson AB III, Venook AP, Adam M,  NCCN Clinical Practice Guidelines in Oncology: Colon Cancer. Version 5.2024. Accessed October 1, 2024. To view the most recent version, visit https:\/\/www.nccn.org"},{"key":"B3","article-title":"NCCN Clinical Practice Guidelines in Oncology: Rectal Cancer. Version 4.2024","author":"Benson AB III","unstructured":"Benson AB III, Venook AP, Adam M,  NCCN Clinical Practice Guidelines in Oncology: Rectal Cancer. Version 4.2024. Accessed October 1, 2024. To view the most recent version, visit https:\/\/www.nccn.org"},{"key":"B4","series-title":"N Engl J Med","first-page":"2207","article-title":"Pembrolizumab in microsatellite-instability-high advanced colorectal cancer","volume":"383","author":"Andr\u00e9 T","year":"2020","unstructured":"Andr\u00e9 T, Shiu KK, Kim TW,  Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med 2020;383:2207\u20132218."},{"key":"B5","series-title":"J Clin Oncol","first-page":"Abstract LBA768","article-title":"Nivolumab plus ipilimumab vs chemotherapy as first-line treatment for microsatellite instability-high\/mismatch repair-deficient metastatic colorectal cancer: first results of the CheckMate 8HW study","volume":"42","author":"Andre T","year":"2024","unstructured":"Andre T, Elez E, Van Cutsem E,  Nivolumab plus ipilimumab vs chemotherapy as first-line treatment for microsatellite instability-high\/mismatch repair-deficient metastatic colorectal cancer: first results of the CheckMate 8HW study. J Clin Oncol 2024;42(Suppl):Abstract LBA768."},{"key":"B6","series-title":"J Clin Oncol","first-page":"161","article-title":"First-line nivolumab plus low-dose ipilimumab for microsatellite instability-high\/mismatch repair-deficient metastatic colorectal cancer: the phase II CheckMate 142 study","volume":"40","author":"Lenz HJ","year":"2022","unstructured":"Lenz HJ, Van Cutsem E, Limon ML,  First-line nivolumab plus low-dose ipilimumab for microsatellite instability-high\/mismatch repair-deficient metastatic colorectal cancer: the phase II CheckMate 142 study. J Clin Oncol 2022;40:161\u2013170."},{"key":"B7","series-title":"J Clin Oncol","first-page":"273","article-title":"Encorafenib plus cetuximab as a new standard of care for previously treated BRAF V600E-mutant metastatic colorectal cancer: updated survival results and subgroup analyses from the BEACON study","volume":"39","author":"Tabernero J","year":"2021","unstructured":"Tabernero J, Grothey A, Van Cutsem E,  Encorafenib plus cetuximab as a new standard of care for previously treated BRAF V600E-mutant metastatic colorectal cancer: updated survival results and subgroup analyses from the BEACON study. J Clin Oncol 2021;39:273\u2013284."},{"key":"B8","series-title":"Lancet Oncol","first-page":"518","article-title":"Pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer (MyPathway): an updated report from a multicentre, open-label, phase 2a, multiple basket study","volume":"20","author":"Meric-Bernstam F","year":"2019","unstructured":"Meric-Bernstam F, Hurwitz H, Raghav KPS,  Pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer (MyPathway): an updated report from a multicentre, open-label, phase 2a, multiple basket study. Lancet Oncol 2019;20:518\u2013530."},{"key":"B9","series-title":"Lancet Oncol","first-page":"496","article-title":"Tucatinib plus trastuzumab for chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer (MOUNTAINEER): a multicentre, open-label, phase 2 study","volume":"24","author":"Strickler JH","year":"2023","unstructured":"Strickler JH, Cercek A, Siena S,  Tucatinib plus trastuzumab for chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer (MOUNTAINEER): a multicentre, open-label, phase 2 study. Lancet Oncol 2023;24:496\u2013508."},{"key":"B10","series-title":"Nat Commun","first-page":"3332.","article-title":"Final results of DESTINY-CRC01 investigating trastuzumab deruxtecan in patients with HER2-expressing metastatic colorectal cancer","volume":"14","author":"Yoshino T","year":"2023","unstructured":"Yoshino T, Di Bartolomeo M, Raghav K,  Final results of DESTINY-CRC01 investigating trastuzumab deruxtecan in patients with HER2-expressing metastatic colorectal cancer. Nat Commun 2023;14:3332."},{"key":"B11","series-title":"J Natl Cancer Inst","first-page":"1","article-title":"ALK, ROS1, and NTRK rearrangements in metastatic colorectal cancer","volume":"109","author":"Pietrantonio F","year":"2017","unstructured":"Pietrantonio F, Di Nicolantonio F, Schrock AB,  ALK, ROS1, and NTRK rearrangements in metastatic colorectal cancer. J Natl Cancer Inst 2017;109:1\u201310."},{"key":"B12","series-title":"Ther Adv Med Oncol","first-page":"252","article-title":"Precision medicine in colorectal cancer: the molecular profile alters treatment strategies","volume":"7","author":"Tran NH","year":"2015","unstructured":"Tran NH, Cavalcante LL, Lubner SJ,  Precision medicine in colorectal cancer: the molecular profile alters treatment strategies. Ther Adv Med Oncol 2015;7:252\u2013262."},{"key":"B13","series-title":"Ann Oncol","first-page":"1535","article-title":"Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study","volume":"22","author":"Bokemeyer C","year":"2011","unstructured":"Bokemeyer C, Bondarenko I, Hartmann J,  Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol 2011;22:1535\u20131546."},{"key":"B14","series-title":"Oncologist","first-page":"663","article-title":"Real-world study of characteristics and treatment outcomes among patients with KRAS p.G12C-mutated or other KRAS mutated metastatic colorectal cancer","volume":"27","author":"Fakih M","year":"2022","unstructured":"Fakih M, Tu H, Hsu H,  Real-world study of characteristics and treatment outcomes among patients with KRAS p.G12C-mutated or other KRAS mutated metastatic colorectal cancer. Oncologist 2022;27:663\u2013674."},{"key":"B15","series-title":"Nature","first-page":"548","article-title":"K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions","volume":"503","author":"Ostrem JM","year":"2013","unstructured":"Ostrem JM, Peters U, Sos ML,  K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 2013;503:548\u2013551."},{"key":"B16","series-title":"Science","first-page":"604","article-title":"Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism","volume":"351","author":"Lito P","year":"2016","unstructured":"Lito P, Solomon M, Li LS,  Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism. Science 2016;351:604\u2013608."},{"key":"B17","series-title":"Cell","first-page":"578","article-title":"Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor","volume":"172","author":"Janes MR","year":"2018","unstructured":"Janes MR, Zhang J, Li LS,  Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor. Cell 2018;172:578\u2013589.e17."},{"key":"B18","series-title":"J Med Chem","first-page":"4468","article-title":"Structure-based design and pharmacokinetic optimization of covalent allosteric inhibitors of the mutant GTPase KRASG12C","volume":"63","author":"Kettle JG","year":"2020","unstructured":"Kettle JG, Bagal SK, Bickerton S,  Structure-based design and pharmacokinetic optimization of covalent allosteric inhibitors of the mutant GTPase KRASG12C. J Med Chem 2020;63:4468\u20134483."},{"key":"B19","series-title":"Cancer Discov","first-page":"54","article-title":"The KRASG12C inhibitor MRTX849 provides insight toward therapeutic susceptibility of KRAS-mutant cancers in mouse models and patients","volume":"10","author":"Hallin J","year":"2020","unstructured":"Hallin J, Engstrom LD, Hargis L,  The KRASG12C inhibitor MRTX849 provides insight toward therapeutic susceptibility of KRAS-mutant cancers in mouse models and patients. Cancer Discov 2020;10:54\u201371."},{"key":"B20","series-title":"J Med Chem","first-page":"52","article-title":"Discovery of a covalent inhibitor of KRASG12C (AMG 510) for the treatment of solid tumors","volume":"63","author":"Lanman BA","year":"2020","unstructured":"Lanman BA, Allen JR, Allen JG,  Discovery of a covalent inhibitor of KRASG12C (AMG 510) for the treatment of solid tumors. J Med Chem 2020;63:52\u201365."},{"key":"B21","series-title":"Mol Cancer Ther","first-page":"Abstract PR014","article-title":"Preliminary safety and anti- tumor activity of RMC-6291, a first-in-class, tri-complex KRASG12C(ON) inhibitor, in patients with or without prior KRASG12C(OFF) inhibitor treatment","volume":"22","author":"J\u00e4nne PA","year":"2023","unstructured":"J\u00e4nne PA, Bigot F, Papadopoulos K,  Preliminary safety and anti- tumor activity of RMC-6291, a first-in-class, tri-complex KRASG12C(ON) inhibitor, in patients with or without prior KRASG12C(OFF) inhibitor treatment. Mol Cancer Ther 2023;22(Suppl):Abstract PR014."},{"key":"B22","series-title":"N Engl J Med","first-page":"2371","article-title":"Sotorasib for lung cancers with KRAS p.G12C mutation","volume":"384","author":"Skoulidis F","year":"2021","unstructured":"Skoulidis F, Li BT, Dy GK,  Sotorasib for lung cancers with KRAS p.G12C mutation. N Engl J Med 2021;384:2371\u20132381."},{"key":"B23","series-title":"Lancet Oncol","first-page":"115","article-title":"Sotorasib for previously treated colorectal cancers with KRASG12C mutation (CodeBreaK100): a prespecified analysis of a single-arm, phase 2 trial","volume":"23","author":"Fakih MG","year":"2022","unstructured":"Fakih MG, Kopetz S, Kuboki Y,  Sotorasib for previously treated colorectal cancers with KRASG12C mutation (CodeBreaK100): a prespecified analysis of a single-arm, phase 2 trial. Lancet Oncol 2022;23:115\u2013124."},{"key":"B24","series-title":"N Engl J Med","first-page":"120","article-title":"Adagrasib in non-small-cell lung cancer harboring a KRASG12C mutation","volume":"387","author":"J\u00e4nne PA","year":"2022","unstructured":"J\u00e4nne PA, Riely GJ, Gadgeel SM,  Adagrasib in non-small-cell lung cancer harboring a KRASG12C mutation. N Engl J Med 2022;387:120\u2013131."},{"key":"B25","series-title":"N Engl J Med","first-page":"44","article-title":"Adagrasib with or without cetuximab in colorectal cancer with mutated KRAS G12C","volume":"388","author":"Yaeger R","year":"2023","unstructured":"Yaeger R, Weiss J, Pelster MS,  Adagrasib with or without cetuximab in colorectal cancer with mutated KRAS G12C. N Engl J Med 2023;388:44\u201354."},{"key":"B26","series-title":"N Engl J Med","first-page":"710","article-title":"Single-agent divarasib (GDC-6036) in solid tumors with a KRAS G12C mutation","volume":"389","author":"Sacher A","year":"2023","unstructured":"Sacher A, LoRusso P, Patel MR,  Single-agent divarasib (GDC-6036) in solid tumors with a KRAS G12C mutation. N Engl J Med 2023;389:710\u2013721."},{"key":"B27","article-title":"Efficacy and safety of olomorasib (LY3537982), a potent and highly selective KRAS G12C inhibitor in KRAS G12C-mutant GI cancers: results from a phase 1 study","author":"Hollebecque A","unstructured":"Hollebecque A, Kuboki Y, Murciano-Goroff YR,  Efficacy and safety of olomorasib (LY3537982), a potent and highly selective KRAS G12C inhibitor in KRAS G12C-mutant GI cancers: results from a phase 1 study. Presented at the 2024 ASCO Gastrointestinal Cancers Symposium; January 18\u201320, 2024; San Francisco, California. Abstract 94."},{"key":"B28","series-title":"Cancer Discov","first-page":"227","article-title":"EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib","volume":"2","author":"Corcoran RB","year":"2012","unstructured":"Corcoran RB, Ebi H, Turke AB,  EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov 2012;2:227\u2013235."},{"key":"B29","series-title":"Cancer Discov","first-page":"1129","article-title":"EGFR blockade reverts resistance to KRASG12C inhibition in colorectal cancer","volume":"10","author":"Amodio V","year":"2020","unstructured":"Amodio V, Yaeger R, Arcella P,  EGFR blockade reverts resistance to KRASG12C inhibition in colorectal cancer. Cancer Discov 2020;10:1129\u20131139."},{"key":"B30","series-title":"Clin Cancer Res","first-page":"1633","article-title":"Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition","volume":"26","author":"Ryan MB","year":"2020","unstructured":"Ryan MB, Fece de la Cruz F, Phat S,  Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition. Clin Cancer Res 2020;26:1633\u20131643."},{"key":"B31","series-title":"N Engl J Med","first-page":"2125","article-title":"Sotorasib plus panitumumab in refractory colorectal cancer with mutated KRAS G12C","volume":"389","author":"Fakih MG","year":"2023","unstructured":"Fakih MG, Salvatore L, Esaki T,  Sotorasib plus panitumumab in refractory colorectal cancer with mutated KRAS G12C. N Engl J Med 2023;389:2125\u20132139."},{"key":"B32","series-title":"Cancer Discov","first-page":"982","article-title":"Efficacy and safety of adagrasib plus cetuximab in patients with KRASG12C-mutated metastatic colorectal cancer","volume":"14","author":"Yaeger R","year":"2024","unstructured":"Yaeger R, Uboha NV, Pelster MS,  Efficacy and safety of adagrasib plus cetuximab in patients with KRASG12C-mutated metastatic colorectal cancer. Cancer Discov 2024;14:982\u2013993."},{"key":"B33","series-title":"Nat Med","first-page":"271","article-title":"Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial","volume":"30","author":"Desai J","year":"2023","unstructured":"Desai J, Alonso G, Kim SH,  Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial. Nat Med 2023;30:271\u2013278."},{"key":"B34","series-title":"Cancer Discov","first-page":"358","article-title":"Clinical acquired resistance to RAF inhibitor combinations in BRAF-mutant colorectal cancer through MAPK pathway alterations","volume":"5","author":"Ahronian LG","year":"2015","unstructured":"Ahronian LG, Sennott EM, Van Allen EM,  Clinical acquired resistance to RAF inhibitor combinations in BRAF-mutant colorectal cancer through MAPK pathway alterations. Cancer Discov 2015;5:358\u2013367."},{"key":"B35","series-title":"Ther Adv Med Oncol","first-page":"17588359221105022.","article-title":"Molecular mechanisms underlying the resistance of BRAF V600E-mutant metastatic colorectal cancer to EGFR\/BRAF inhibitors","volume":"14","author":"Xu T","year":"2022","unstructured":"Xu T, Wang X, Wang Z,  Molecular mechanisms underlying the resistance of BRAF V600E-mutant metastatic colorectal cancer to EGFR\/BRAF inhibitors. Ther Adv Med Oncol 2022;14:17588359221105022."},{"key":"B36","series-title":"Cancer Discov","first-page":"41","article-title":"Molecular characterization of acquired resistance to KRASG12C-EGFR inhibition in colorectal cancer","volume":"13","author":"Yaeger R","year":"2023","unstructured":"Yaeger R, Mezzadra R, Sinopoli J,  Molecular characterization of acquired resistance to KRASG12C-EGFR inhibition in colorectal cancer. Cancer Discov 2023;13:41\u201355."},{"key":"B37","series-title":"J Clin Oncol","first-page":"Abstract 8510","article-title":"Efficacy and safety of olomorasib (LY3537982), a second-generation KRAS G12C inhibitor (G12Ci), in combination with pembrolizumab in patients with KRAS G12C-mutant advanced NSCLC","volume":"42","author":"Burns TF","year":"2024","unstructured":"Burns TF, Dragnev KH, Fujiwara Y,  Efficacy and safety of olomorasib (LY3537982), a second-generation KRAS G12C inhibitor (G12Ci), in combination with pembrolizumab in patients with KRAS G12C-mutant advanced NSCLC. J Clin Oncol 2024;42(Suppl):Abstract 8510."}],"container-title":["Journal of the National Comprehensive Cancer Network"],"original-title":[],"link":[{"URL":"https:\/\/jnccn.org\/view\/journals\/jnccn\/23\/1\/article-e247067.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/jnccn.org\/downloadpdf\/journals\/jnccn\/23\/1\/article-e247067.xml","content-type":"text\/html","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/jnccn.org\/downloadpdf\/journals\/jnccn\/23\/1\/article-e247067.xml","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,15]],"date-time":"2025-01-15T13:55:37Z","timestamp":1736949337000},"score":1,"resource":{"primary":{"URL":"https:\/\/jnccn.org\/view\/journals\/jnccn\/23\/1\/article-e247067.xml"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1]]},"references-count":37,"journal-issue":{"issue":"1"},"URL":"https:\/\/doi.org\/10.6004\/jnccn.2024.7067","relation":{},"ISSN":["1540-1405","1540-1413"],"issn-type":[{"value":"1540-1405","type":"print"},{"value":"1540-1413","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1]]}}}