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

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/CRA

SUBMITTER: Wang J 

PROVIDER: S-EPMC11645146 | biostudies-literature | 2024 Oct

REPOSITORIES: biostudies-literature