Abstract
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.
Authors
Jiawei Wang, Huogang Wang, Wei Zhou, Xin Luo, Huijuan Wang, Qing Meng, Jiaxin Chen, Xiaoyu Chen, Yingqiang Liu, David W. Chan, Zhenyu Ju, Zhangfa Song
Graphical abstract
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)