MOGAT3-mediated DAG accumulation drives acquired resistance to anti-BRAF/anti-EGFR therapy in BRAFV600E-mutant metastatic colorectal cancer.

Autor: Wang J; Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.; Key Laboratory of Biological Treatment of Zhejiang Province, Hangzhou, China.; Key Laboratory of Integrated Traditional Chinese and Western Medicine Research on Anorectal Diseases of Zhejiang Province, Hangzhou, China., Wang H; Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.; Key Laboratory of Biological Treatment of Zhejiang Province, Hangzhou, China.; Key Laboratory of Integrated Traditional Chinese and Western Medicine Research on Anorectal Diseases of Zhejiang Province, Hangzhou, China., Zhou W; Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.; Key Laboratory of Biological Treatment of Zhejiang Province, Hangzhou, China.; Key Laboratory of Integrated Traditional Chinese and Western Medicine Research on Anorectal Diseases of Zhejiang Province, Hangzhou, China., Luo X; Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China., Wang H; Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.; Key Laboratory of Biological Treatment of Zhejiang Province, Hangzhou, China.; Key Laboratory of Integrated Traditional Chinese and Western Medicine Research on Anorectal Diseases of Zhejiang Province, Hangzhou, China., Meng Q; Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.; Key Laboratory of Biological Treatment of Zhejiang Province, Hangzhou, China.; Key Laboratory of Integrated Traditional Chinese and Western Medicine Research on Anorectal Diseases of Zhejiang Province, Hangzhou, China., Chen J; Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China., Chen X; Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.; Key Laboratory of Biological Treatment of Zhejiang Province, Hangzhou, China.; Key Laboratory of Integrated Traditional Chinese and Western Medicine Research on Anorectal Diseases of Zhejiang Province, Hangzhou, China., Liu Y; Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.; Key Laboratory of Biological Treatment of Zhejiang Province, Hangzhou, China.; Key Laboratory of Integrated Traditional Chinese and Western Medicine Research on Anorectal Diseases of Zhejiang Province, Hangzhou, China., Chan DW; School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China., Ju Z; Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, China., Song Z; Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.; Key Laboratory of Biological Treatment of Zhejiang Province, Hangzhou, China.; Key Laboratory of Integrated Traditional Chinese and Western Medicine Research on Anorectal Diseases of Zhejiang Province, Hangzhou, China.
Jazyk: angličtina
Zdroj: The Journal of clinical investigation [J Clin Invest] 2024 Oct 22; Vol. 134 (24). Date of Electronic Publication: 2024 Oct 22.
DOI: 10.1172/JCI182217
Abstrakt: BRAFV600E-mutant metastatic colorectal cancer (mCRC) is associated with poor prognosis. The combination of anti-BRAF/anti-EGFR (encorafenib/cetuximab) treatment for patients with BRAFV600E-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-mediated (MOGAT3-mediated) diacylglycerol (DAG) accumulation contributed to acquired resistance to encorafenib/cetuximab by dissecting a BRAFV600E-mutant mCRC patient-derived xenograft (PDX) model exposed to encorafenib/cetuximab administration. Mechanistically, the upregulated MOGAT3 promoted DAG synthesis and reduced fatty acid oxidation-promoting DAG accumulation and activated PKCα/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 PKCα/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 BRAFV600E-mutant mCRC, which interrupted PKCα/CRAF/MEK/ERK signaling. These findings reveal the critical role of the metabolite DAG as a modulator of encorafenib/cetuximab efficacy in BRAFV600E-mutant mCRC, suggesting that fenofibrate might prove beneficial for resistant BRAFV600E-mutant mCRC patients.
Databáze: MEDLINE