BRAFV600E-mutant metastatic colorectal cancer (mCRC) is associated with poor prognosis. The combination of anti-BRAF/EGFR (encorafenib/cetuximab) treatment for patients with BRAFV600E-mutant mCRC improved 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 (MOGAT3) mediated diacylglycerol (DAG) accumulation contributed to acquired resistance to encorafenib/cetuximab by dissecting BRAFV600E-mutant mCRC patient-derived xenograft (PDX) model exposed to encorafenib/cetuximab administration. Mechanistically, upregulated MOGAT3 promotes DAG synthesis and reduces fatty acid oxidation (FAO)-promoting DAG accumulation and activating PKCα-CRAF-MEK-ERK, driving acquired resistance. Resistance-induced hypoxia promotes MOGAT3 transcriptional elevation; simultaneously, MOGAT3-mediated DAG accumulation increases HIF1A expression in translation level through PKCα-CRAF-eIF4E activation, strengthening the resistance status. Intriguingly, reducing intratumoral DAG by fenofibrate or Pf-06471553 restores the antitumor efficacy of encorafenib/cetuximab on resistant BRAFV600E-mutant mCRC, interrupted PKCα-CRAF-MEK-ERK signaling. These findings reveal the critical metabolite DAG as a modulator of encorafenib/cetuximab efficacy in BRAFV600E-mutant mCRC, suggesting that fenofibrate may prove beneficial for resistant BRAFV600E-mutant mCRC patients.

中文翻译：

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MOGAT3 介导的 DAG 积累驱动 BRAFV600E 突变转移性结直肠癌对抗 BRAF/EGFR 治疗的获得性耐药。


BRAFV600E突变转移性结直肠癌 （mCRC） 与不良预后相关。抗 BRAF/EGFR （encorafenib/cetuximab） 联合治疗 BRAFV600E 突变 mCRC 患者改善了临床获益;不幸的是，不可避免的获得性耐药限制了治疗结果，并且其机制尚未得到验证。在这里，我们发现单酰基甘油 O-酰基转移酶 3 （MOGAT3） 介导的甘油二酯 （DAG） 积累通过解剖暴露于 encorafenib/西妥昔单抗给药的 BRAFV600E 突变 mCRC 患者来源的异种移植物 （PDX） 模型，导致对 encorafenib/西妥昔单抗的获得性耐药。从机制上讲，上调的 MOGAT3 促进 DAG 合成并减少脂肪酸氧化 （FAO） 促进 DAG 积累并激活 PKCα-CRAF-MEK-ERK，从而驱动获得性耐药。抵抗诱导的缺氧促进 MOGAT3 转录升高;同时，MOGAT3 介导的 DAG 积累通过 PKCα-CRAF-eIF4E 激活增加翻译水平 HIF1A 的表达，从而加强耐药状态。有趣的是，通过非诺贝特或 Pf-06471553 减少瘤内 DAG 可恢复 encorafenib/西妥昔单抗对耐药 BRAFV600E 突变 mCRC、中断的 PKCα-CRAF-MEK-ERK 信号传导的抗肿瘤疗效。这些发现揭示了关键代谢物 DAG 作为 encorafenib/西妥昔单抗在 BRAFV600E 突变 mCRC 疗效的调节剂，表明非诺贝特可能证明对耐药 BRAFV600E 突变 mCRC 患者有益。