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

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/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

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Figure 1

Encorafenib- and cetuximab-resistant BRAFV600E-mutant mCRC tumors exhibited abnormal lipid-metabolizing activity.

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Encorafenib- and cetuximab-resistant BRAFV600E-mutant mCRC tumors exhibi...
(A) Patient-derived BRAFV600E-mutant mCRC samples: Computed tomography picture shows primary tumor location (left) and H&E morphology of original primary and PDX tumor mass (right). (B) Mean tumor volumes (±SEM) of BRAFV600E-mutant mCRC PDXs treated with encorafenib and cetuximab relative to baseline (T0) (n = 6). (C) Bubble plot showing KEGG pathways (https://www.genome.jp/kegg/pathway.html) of upregulated genes enriched in resistant PDX tumors versus sensitive PDX tumors based on RNA-seq data (n = 3). (D) Heatmap showing metabolic pathways genes related to C (n = 3). (E) Bar chart presenting a classification of metabolic pathways genes related to D. (F) Gene set enrichment analysis (GSEA) of resistant tumors versus sensitive tumors (n = 3) showing enhanced lipid metabolic process. Normalized enrichment score (NES) and nominal P value are provided according to GSEA. (G) Lipid droplet content of tumors was assessed by Nile red staining over 3 periods. Representative images are shown from 3 independent experiments. Scale bar: 20 μm. (H) RKO, RKO EC-R, HT29, and HT29 EC-R cells were stained with BODIPY 493/503 (green). Representative images are shown from 3 independent experiments. Scale bar: 10 μm.