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MOGAT3-mediated DAG accumulation drives acquired resistance to anti-BRAF/anti-EGFR therapy in BRAFV600E-mutant metastatic colorectal cancer
Jiawei Wang, … , Zhenyu Ju, Zhangfa Song
Jiawei Wang, … , Zhenyu Ju, Zhangfa Song
Published October 22, 2024
Citation Information: J Clin Invest. 2024;134(24):e182217. https://doi.org/10.1172/JCI182217.
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Research Article Gastroenterology Article has an altmetric score of 8

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

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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 3

MOGAT3-mediated DAG elevation determines anti-BRAF/EGFR treatment failure in BRAFV600E-mutant mCRC tumors.

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MOGAT3-mediated DAG elevation determines anti-BRAF/EGFR treatment failur...
(A) Representative IHC images of MOGAT3 in baseline, sensitive, and resistant tumor tissues. Scale bar: 100 μm. (B) Top: Western blots showing protein expression of MOGAT3 in RKO, RKO EC-R, HT29, and HT29 EC-R cells. Representative blots are shown. MOGAT3KO RKO EC-R and HT29 EC-R, along with RKO EC-R-CTRL and HT29 EC-R-CTRL cell lines, were exposed to 2 μM encorafenib/4 μM cetuximab for 96 hours. Bottom: Relative OD value was assessed to determine cell viability by the CCK-8 assay (n = 3). (C–E) Xenograft tumor size in nude mice inoculated with RKO EC-R cells (CTRL) or MOGAT3KO RKO EC-R cells, and treated with just encorafenib-cetuximab or encorafenib-cetuximab in combination with i.p. injection of DAG. (C) Tumor weight, (D) tumor DAG level, and (E) tumor growth in nude mice (n = 6). (F–H) Xenograft tumor size in nude mice inoculated with RKO cells (Nc) or RKO Oe-MOGAT3 cells and treated with encorafenib-cetuximab. (F) Xenograft tumor weight, (G) DAG level in tumor tissues, and (H) tumor growth (n = 6). (I–K) Xenograft tumor size in nude mice inoculated with encorafenib-cetuximab–resistant BRAFV600E-mutant mCRC tumor tissues. PDXs were treated with vehicle (PBS), 20 mg/kg encorafenib/20 mg/kg cetuximab, or MOGAT3 inhibitor PF-06471553 (Pf; 50 mg/kg) alone or in combination with encorafenib-cetuximab. (I) Xenograft tumor weight, (J) DAG level in tumor tissues, and (K) growth in nude mice (n = 6). The data are presented as mean ± SEM of 3 independent experiments. NS, no significance. ***P < 0.001 by 2-way ANOVA with Tukey’s multiple-comparison test (B, E, H, and K), 1-way ANOVA with Tukey’s multiple-comparison test (C, D, I, and J), or 2-tailed, unpaired t test (F and G).

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