{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T11:33:24Z","timestamp":1790422404436,"version":"4.1.0"},"reference-count":45,"publisher":"American Society for Clinical Investigation","issue":"24","license":[{"start":{"date-parts":[[2024,12,16]],"date-time":"2024-12-16T00:00:00Z","timestamp":1734307200000},"content-version":"vor","delay-in-days":55,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["No.82273265"],"award-info":[{"award-number":["No.82273265"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,12,16]]},"abstract":"<jats:p>\n                    <jats:italic>\n                      <jats:italic>\n                        BRAF\n                        <jats:sup>V600E<\/jats:sup>\n                      <\/jats:italic>\n                    <\/jats:italic>\n                    -mutant metastatic colorectal cancer (mCRC) is associated with poor prognosis. The combination of anti-BRAF\/anti-EGFR (encorafenib\/cetuximab) treatment for patients with\n                    <jats:italic>\n                      <jats:italic>\n                        BRAF\n                        <jats:sup>V600E<\/jats:sup>\n                      <\/jats:italic>\n                    <\/jats:italic>\n                    -mutant mCRC improves clinical benefits; unfortunately, inevitable acquired resistance limits the treatment outcome, and the mechanism has not been validated. Here, we discovered that monoacylglycerol O-acyltransferase 3\u2013mediated (MOGAT3-mediated) diacylglycerol (DAG) accumulation contributed to acquired resistance to encorafenib\/cetuximab by dissecting a\n                    <jats:italic>\n                      <jats:italic>\n                        BRAF\n                        <jats:sup>V600E<\/jats:sup>\n                      <\/jats:italic>\n                    <\/jats:italic>\n                    -mutant mCRC patient\u2013derived xenograft (PDX) model exposed to encorafenib\/cetuximab administration. Mechanistically, the upregulated MOGAT3 promoted DAG synthesis and reduced fatty acid oxidation\u2013promoting DAG accumulation and activated PKC\u03b1\/CRAF\/MEK\/ERK signaling, driving acquired resistance. Resistance-induced hypoxia promoted MOGAT3 transcriptional elevation; simultaneously, MOGAT3-mediated DAG accumulation increased HIF1A expression at the translation level through PKC\u03b1\/CRAF\/eIF4E activation, strengthening the resistance status. Intriguingly, reducing intratumoral DAG with fenofibrate or PF-06471553 restored the antitumor efficacy of encorafenib\/cetuximab in resistant\n                    <jats:italic>\n                      <jats:italic>\n                        BRAF\n                        <jats:sup>V600E<\/jats:sup>\n                      <\/jats:italic>\n                    <\/jats:italic>\n                    -mutant mCRC, which interrupted PKC\u03b1\/CRAF\/MEK\/ERK signaling. These findings reveal the critical role of the metabolite DAG as a modulator of encorafenib\/cetuximab efficacy in\n                    <jats:italic>\n                      <jats:italic>\n                        BRAF\n                        <jats:sup>V600E<\/jats:sup>\n                      <\/jats:italic>\n                    <\/jats:italic>\n                    -mutant mCRC, suggesting that fenofibrate might prove beneficial for resistant\n                    <jats:italic>\n                      <jats:italic>\n                        BRAF\n                        <jats:sup>V600E<\/jats:sup>\n                      <\/jats:italic>\n                    <\/jats:italic>\n                    -mutant mCRC patients.\n                  <\/jats:p>","DOI":"10.1172\/jci182217","type":"journal-article","created":{"date-parts":[[2024,10,22]],"date-time":"2024-10-22T12:01:12Z","timestamp":1729598472000},"source":"Crossref","is-referenced-by-count":10,"title":["MOGAT3-mediated DAG accumulation drives acquired resistance to anti-BRAF\/anti-EGFR therapy in BRAFV600E-mutant metastatic colorectal cancer"],"prefix":"10.1172","volume":"134","author":[{"given":"Jiawei","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China."},{"name":"Key Laboratory of Biological Treatment of Zhejiang Province, Hangzhou, China."},{"name":"Key Laboratory of Integrated Traditional Chinese and Western Medicine Research on Anorectal Diseases of Zhejiang Province, Hangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huogang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China."},{"name":"Key Laboratory of Biological Treatment of Zhejiang Province, Hangzhou, China."},{"name":"Key Laboratory of Integrated Traditional Chinese and Western Medicine Research on Anorectal Diseases of Zhejiang Province, Hangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China."},{"name":"Key Laboratory of Biological Treatment of Zhejiang Province, Hangzhou, China."},{"name":"Key Laboratory of Integrated Traditional Chinese and Western Medicine Research on Anorectal Diseases of Zhejiang Province, Hangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huijuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China."},{"name":"Key Laboratory of Biological Treatment of Zhejiang Province, Hangzhou, China."},{"name":"Key Laboratory of Integrated Traditional Chinese and Western Medicine Research on Anorectal Diseases of Zhejiang Province, Hangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Meng","sequence":"additional","affiliation":[{"name":"Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China."},{"name":"Key Laboratory of Biological Treatment of Zhejiang Province, Hangzhou, China."},{"name":"Key Laboratory of Integrated Traditional Chinese and Western Medicine Research on Anorectal Diseases of Zhejiang Province, Hangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China."},{"name":"Key Laboratory of Biological Treatment of Zhejiang Province, Hangzhou, China."},{"name":"Key Laboratory of Integrated Traditional Chinese and Western Medicine Research on Anorectal Diseases of Zhejiang Province, Hangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingqiang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of 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