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Updated: Apr 7, 2026

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
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Metabolic Rewiring by Oncogenic BRAF V600E Links Ketogenesis Pathway to BRAF-MEK1 Signaling

Hee-Bum Kang1, Jun Fan1, Ruiting Lin1

  • 1Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.

Molecular Cell
|July 7, 2015
PubMed

Insights

Oncogenic BRAF V600E drives cancer by upregulating the ketogenic enzyme HMGCL. Suppressing HMGCL selectively halts BRAF V600E melanoma growth, revealing a new therapeutic target.

Area of Science:

  • Oncology
  • Metabolic pathways
  • Cancer signaling

Background:

  • Many cancers exhibit metabolic alterations like the Warburg effect.
  • The necessity of oncogene-specific metabolic changes for tumor growth is not fully understood.

Purpose of the Study:

  • To investigate the role of oncogene-specific metabolic alterations in tumor development.
  • To identify synthetic lethal interactions involving oncogenic BRAF V600E.

Main Methods:

  • Demonstrated a synthetic lethal interaction between oncogenic BRAF V600E and 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL).
  • Assessed HMGCL expression in BRAF V600E-positive human melanoma and hairy cell leukemia cells.
  • Investigated the mechanism of HMGCL upregulation by BRAF V600E via Oct-1 and its effect on MEK-ERK signaling.

Main Results:

  • HMGCL expression is upregulated in BRAF V600E-positive cancers.
  • HMGCL suppression selectively reduces proliferation and tumor growth in BRAF V600E melanoma cells.
  • BRAF V600E upregulates HMGCL through Oct-1, increasing acetoacetate, which enhances BRAF V600E binding to MEK1, promoting MEK-ERK signaling.

Conclusions:

  • Oncogenic BRAF V600E utilizes a mutation-specific metabolic rewiring mechanism involving the Oct-1-HMGCL-acetoacetate axis.
  • This axis selectively promotes BRAF V600E-dependent tumor development.
  • Findings reveal a novel pathway linking metabolic and signaling networks in BRAF V600E-driven cancers.

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