{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T12:59:52Z","timestamp":1793710792025,"version":"4.6.1"},"reference-count":18,"publisher":"National Academy of Sciences","issue":"18","license":[{"start":{"date-parts":[[2022,4,26]],"date-time":"2022-04-26T00:00:00Z","timestamp":1650931200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,5,3]]},"abstract":"<jats:title>Significance<\/jats:title>\n                  <jats:p>\n                    KRAS\n                    <jats:sup>G12C<\/jats:sup>\n                    inhibitors have demonstrated promising efficacy in non\u2013small-cell lung cancer patients harboring the KRAS\n                    <jats:sup>G12C<\/jats:sup>\n                    mutation. However, the mechanism of resistance remains to be fully understood. To understand the consequences of single amino acid changes within KRAS\n                    <jats:sup>G12C<\/jats:sup>\n                    , we conducted a saturation mutagenesis screen of the KRAS\n                    <jats:sup>G12C<\/jats:sup>\n                    protein and assessed the mutational impact on drug sensitivity. Not only did our screen reveal resistant hits that were identified from patients\u2019 samples (V8L, C12F, R68S, H95D, H95R, and Y96C), but we also discovered variants that sensitize the inhibition. Furthermore, we examined the human genetics databases and identified germline or somatic KRAS mutations that appear among the strong resistance hits. Our study positions future drug discovery targeting KRAS\n                    <jats:sup>G12C<\/jats:sup>\n                    toward focusing on inhibitors preserving potency against resistance mutations at key residues.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2120512119","type":"journal-article","created":{"date-parts":[[2022,4,26]],"date-time":"2022-04-26T14:48:40Z","timestamp":1650984520000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":29,"title":["A saturation mutagenesis screen uncovers resistant and sensitizing secondary\n                    <i>KRAS<\/i>\n                    mutations to clinical KRAS\n                    <sup>G12C<\/sup>\n                    inhibitors"],"prefix":"10.1073","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8499-6914","authenticated-orcid":false,"given":"Siyu","family":"Feng","sequence":"first","affiliation":[{"name":"Department of Discovery Oncology, Genentech, Inc., South San Francisco, CA 94080"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2560-5412","authenticated-orcid":false,"given":"Marinella G.","family":"Callow","sequence":"additional","affiliation":[{"name":"Department of Discovery Oncology, Genentech, Inc., South San Francisco, CA 94080"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Philippe","family":"Fortin","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics, Genentech, Inc., South San Francisco, CA 94080"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7859-3489","authenticated-orcid":false,"given":"Zia","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Genentech, Inc., South San Francisco, CA 94080"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Bray","sequence":"additional","affiliation":[{"name":"Foundation Medicine, Inc., Cambridge, MA 02141"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mike","family":"Costa","sequence":"additional","affiliation":[{"name":"Department of Discovery Oncology, Genentech, Inc., South San Francisco, CA 94080"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA 94080"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiru","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Structural Biology, Genentech, Inc., South San Francisco, CA 94080"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Evangelista","sequence":"additional","affiliation":[{"name":"Department of Discovery Oncology, Genentech, Inc., South San Francisco, CA 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