{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T22:01:18Z","timestamp":1785016878011,"version":"3.55.0"},"reference-count":17,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:00:00Z","timestamp":1784505600000},"content-version":"vor","delay-in-days":12,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Hebei Province Medical-Research-Enterprise Joint Innovation Special Project","award":["LH20250028"],"award-info":[{"award-number":["LH20250028"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Acquired resistance limits the long-term efficacy of KRAS G12C inhibitors in metastatic colorectal cancer (mCRC). While feedback signaling is a known resistance driver, the clinical evolution of structural alterations within the drug-binding pocket remains poorly characterized.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Case presentation<\/jats:title>\n                    <jats:p>We present a patient with microsatellite-stable (MSS) KRAS G12C-mutated mCRC who progressed after 9.3\u2009months of sequential KRAS G12C inhibitor monotherapy. Comparative molecular profiling of baseline tissue and post-progression plasma ctDNA identified the de novo emergence of concurrent KRAS Y96S and Y96C mutations. These polyclonal Switch II pocket alterations, absent in pretreatment specimens, indicated convergent evolution under therapeutic selective pressure. A rationale-based salvage therapy utilizing vertical MAPK pathway blockade (sotorasib, cetuximab, and trametinib) failed to achieve durable control (PFS: 1.9\u2009months), confirming biological refractoriness.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The acquisition of polyclonal KRAS Y96S\/C mutations represents a definitive structural resistance mechanism that compromises the efficacy of intensified vertical pathway blockade. The discordance between tissue and liquid biopsy findings underscores the necessity of plasma-based monitoring to capture spatial heterogeneity. These findings suggest that overcoming convergent Switch II pocket remodeling requires next-generation inhibitors with distinct binding modes rather than further pathway intensification.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/oncolo\/oyag263","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T11:42:44Z","timestamp":1784288564000},"source":"Crossref","is-referenced-by-count":0,"title":["First report of dual KRAS Y96C\/Y96S resistance mutations detected by liquid biopsy in KRAS G12C\u2013mutant metastatic colorectal cancer"],"prefix":"10.1093","volume":"31","author":[{"given":"ZhiYu","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, Affiliated Hospital of Hebei University , Baoding, Hebei, 071000,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Affiliated Hospital of Hebei University , Baoding, Hebei, 071000,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Integrated Traditional Chinese and Western Medicine, Affiliated Hospital of Hebei University , Baoding, Hebei, 071000,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Qin","sequence":"additional","affiliation":[{"name":"Experimental Center, Affiliated Hospital of Hebei University , Baoding, Hebei, 071000,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"ZhiGui","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Affiliated Hospital of Hebei University , Baoding, Hebei, 071000,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Huo","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Affiliated Hospital of Hebei University , Baoding, Hebei, 071000,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Affiliated Hospital of Hebei University , Baoding, Hebei, 071000,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Lu","sequence":"additional","affiliation":[{"name":"Burning Rock Biotech Department of Medicine, , Guangzhou 510300,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Li","sequence":"additional","affiliation":[{"name":"Burning Rock Biotech Department of Medicine, , Guangzhou 510300,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4720-258X","authenticated-orcid":false,"given":"ShenYong","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Affiliated Hospital of Hebei University , Baoding, Hebei, 071000,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,7,20]]},"reference":[{"key":"2026072517463537900_oyag263-B1","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1016\/S1470-2045(21)00605-7","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","year":"2022","journal-title":"Lancet 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