{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T21:55:49Z","timestamp":1792706149204,"version":"4.5.0"},"reference-count":78,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,1,5]],"date-time":"2021-01-05T00:00:00Z","timestamp":1609804800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["A25254"],"award-info":[{"award-number":["A25254"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["A20465"],"award-info":[{"award-number":["A20465"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>KRAS is one of the most common human oncogenes, but concerted efforts to produce direct inhibitors have largely failed, earning KRAS the title of \u201cundruggable\u201d. Recent efforts to produce subtype specific inhibitors have been more successful, and several KRASG12C inhibitors have reached clinical trials, including adagrasib and sotorasib, which have shown early evidence of efficacy in patients. Lessons from other inhibitors of the RAS pathway suggest that the effect of these drugs will be limited in vivo by the development of drug resistance, and pre-clinical studies of G12C inhibitors have identified evidence of this. In this review we discuss the current evidence for G12C inhibitors, the mechanisms of resistance to G12C inhibitors and potential approaches to overcome them. We discuss possible targets of combination therapy, including SHP2, receptor tyrosine kinases, downstream effectors and PD1\/PDL1, and review the ongoing clinical trials investigating these inhibitors.<\/jats:p>","DOI":"10.3390\/cancers13010151","type":"journal-article","created":{"date-parts":[[2021,1,5]],"date-time":"2021-01-05T10:35:12Z","timestamp":1609842912000},"page":"151","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":119,"title":["Mechanisms of Resistance to KRASG12C Inhibitors"],"prefix":"10.3390","volume":"13","author":[{"given":"Victoria","family":"Dunnett-Kane","sequence":"first","affiliation":[{"name":"Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester M23 9LT, UK"},{"name":"Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pantelis","family":"Nicola","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UK"},{"name":"Division of Molecular and Clinical Cancer Sciences, University of Manchester, Manchester M13 9PL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiona","family":"Blackhall","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UK"},{"name":"Division of Molecular and Clinical Cancer Sciences, University of Manchester, Manchester M13 9PL, UK"},{"name":"Cancer Research UK Lung Cancer Centre of Excellence, Manchester M20 4BX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin","family":"Lindsay","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UK"},{"name":"Division of Molecular and Clinical Cancer Sciences, University of Manchester, Manchester M13 9PL, UK"},{"name":"Cancer Research UK Lung Cancer Centre of Excellence, Manchester M20 4BX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1242\/jcs.182873","article-title":"RAS isoforms and mutations in cancer at a glance","volume":"129","author":"Hobbs","year":"2016","journal-title":"J. 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