{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T15:07:36Z","timestamp":1790089656277,"version":"4.0.1"},"reference-count":10,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>RAF1 alterations are rare in metastatic colorectal cancer (mCRC), occurring in roughly 0.5% of cases, and lack established treatment guidance. We present a patient with RAF1 S257L\u2013mutated, RAS wild-type mCRC and concurrent type 1 Gaucher disease, whose baseline cytopenias precluded standard chemotherapy and clinical-trial enrollment. After progression on fluoropyrimidine-, oxaliplatin-, and irinotecan-based regimens (the latter with the anti-EGFR antibody panitumumab) complicated by recurrent neutropenic sepsis, he received off-label avutometinib and defactinib (an oral RAF\/MEK clamp inhibitor plus a FAK inhibitor) combined with cetuximab. He achieved a radiographic response, biomarker decline, hematologic recovery, and improvement in ECOG performance status from 3 to 0, with benefit lasting approximately 6\u2009months. At progression, circulating tumor DNA revealed persistence of RAF1 S257L at high allele fraction with RAF1 amplification, together with newly acquired EGFR ectodomain mutations, KRAS alterations, and a MAP2K1 alteration\u2014a polyclonal pattern of convergent MAPK\/EGFR reactivation. This case illustrates how a molecular tumor board can translate a rare driver into a rational, individualized regimen and how serial liquid biopsy informs resistance and next steps.<\/jats:p>","DOI":"10.1093\/oncolo\/oyag335","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T11:44:59Z","timestamp":1787139899000},"source":"Crossref","is-referenced-by-count":0,"title":["RAF\/MEK clamp inhibition with avutometinib and cetuximab in RAF1 S257L\u2013mutated, anti-EGFR\u2013refractory metastatic colorectal cancer in Gaucher\u2019s disease"],"prefix":"10.1093","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3060-7132","authenticated-orcid":false,"given":"Ashley","family":"Rose","sequence":"first","affiliation":[{"name":"Lenox Hill Hospital , New York, NY 10075,","place":["United States"]},{"name":"Northwell Health Cancer Center , New York, NY 11042,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7631-4770","authenticated-orcid":false,"given":"Alix","family":"Rosenberg","sequence":"additional","affiliation":[{"name":"Donald and Barbara Zucker School of Medicine at Hofstra University , New York, NY 11549,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Udhayvir Singh","family":"Grewal","sequence":"additional","affiliation":[{"name":", Winship Cancer Institute of Emory University Department of Hematology Oncology , Atlanta, GA 30322,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4843-4639","authenticated-orcid":false,"given":"Timothy J","family":"Brown","sequence":"additional","affiliation":[{"name":"UT Southwestern Medical Center Department of Hematology Oncology, , Dallas, TX 75390,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2089-8236","authenticated-orcid":false,"given":"Nicholas","family":"Hornstein","sequence":"additional","affiliation":[{"name":"Northwell Health Cancer Center , New York, NY 11042,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,8,19]]},"reference":[{"key":"2026092210522593800_oyag335-B1","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1111\/bjh.12804","article-title":"Gaucher disease: haematological presentations and complications","volume":"165","author":"Thomas","year":"2014","journal-title":"Br J Haematol"},{"key":"2026092210522593800_oyag335-B2","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1002\/gcc.22813","article-title":"The extended spectrum of RAS-MAPK pathway mutations in colorectal cancer","volume":"59","author":"Costigan","year":"2020","journal-title":"Genes 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cancer","volume":"66","author":"Borovski","year":"2017","journal-title":"Gut"},{"key":"2026092210522593800_oyag335-B6","doi-asserted-by":"publisher","first-page":"1649","DOI":"10.1038\/s41388-023-02683-w","article-title":"RAF1 contributes to cell proliferation and STAT3 activation in colorectal cancer independently of microsatellite and KRAS status","volume":"42","author":"Dorard","year":"2023","journal-title":"Oncogene"},{"key":"2026092210522593800_oyag335-B7","doi-asserted-by":"publisher","first-page":"2782","DOI":"10.1200\/JCO-25-00112","article-title":"Efficacy and safety of avutometinib\u2009\u00b1\u2009defactinib in recurrent low-grade serous ovarian cancer (RAMP 201)","volume":"43","author":"Banerjee","year":"2025","journal-title":"J Clin Oncol"},{"key":"2026092210522593800_oyag335-B8","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1200\/JCO.2025.43.4_suppl.199","article-title":"Avutometinib plus cetuximab after chemotherapy in KRAS-mutated metastatic colorectal 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