Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
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

  • Text
  • PDF
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

×

Figure 4

Highly expressed MOGAT3 promotes lipid synthesis and inhibits lipid OXPHOS, resulting in DAG accumulation.

Options: View larger image (or click on image) Download as PowerPoint
Highly expressed MOGAT3 promotes lipid synthesis and inhibits lipid OXPH...
(A) Schematic diagram of the main DAG synthesis pathway. (B) Western blot showing the protein expression levels of LPIN1 and MOGAT3 in RKO and RKO EC-R cells. A representative blots is shown. (C) DAG level in RKO EC-R MOGAT3KO CDX (n = 6). (D) Oxygen consumption rate (OCR) in RKO and RKO EC-R cells. Oligo, oligomycin; FCCP, carbonyl cyanide 4-trifluoromethoxy-phenylhydrazone; Rot, rotenone. (E) OXPHOS-related indicators were quantified (n = 4). (F) OCR in RKO EC-R and RKO EC-R MOGAT3KO cells. (G) OXPHOS-related indicators were quantified (n = 8). (H–K) FAO assay of RKO and RKO EC-R cells (H) and RKO EC-R MOGAT3KO cells (J). Cells treated with FCCP were used as the positive control, and cells treated with etomoxir (Eto) were used as the negative control. (I and K) Graphs show relative FAO rates (n = 3). The data are presented as mean ± SEM of 3 independent experiments. NS, no significance. **P < 0.01; ***P < 0.001 by 2-tailed, unpaired t test (C, E, G, I, and K) or 2-way ANOVA with Tukey’s multiple-comparison test (H and J).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Blogged by 1
Referenced by 1 Bluesky users
8 readers on Mendeley
See more details