Ketogenesis Drives BRAF–MEK1 Signaling in BRAF^V600E-Positive Cancers

More than half of human melanomas express oncogenic BRAF^V600E, which promotes cell proliferation via BRAF–MEK1 signaling. Mutant BRAF and MEK inhibitors have shown success in clinical trials for BRAF^V600E-positive melanoma, but drug resistance limits their long-term efficacy. Using systematic RNA interference screens, Kang, Fan, Lin, and colleagues identified the ketogenic enzyme 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL) as a synthetic lethal partner of BRAF^V600E in melanoma cells. HMGCL was upregulated in BRAF^V600E-expressing melanoma cell lines and in primary BRAF^V600E-positive melanoma and hairy cell leukemia tumors compared with BRAF wild-type–expressing samples. Knockdown of HMGCL attenuated cell proliferation in BRAF^V600E-mutant cells but not in BRAF wild-type cells and decreased phosphorylation of MEK1 and ERK1/2, suggesting that HMGCL activity in ketogenesis specifically regulates the BRAF–MEK–ERK signaling cascade to promote BRAF^V600E-induced transformation. HMGCL depletion led to decreased intracellular levels of its metabolic product, acetoacetate (AA), and addition of AA selectively restored cell proliferation and phosphorylation of MEK1 and ERK1/2 only in BRAF^V600E-expressing cells. Mechanistically, treatment with AA increased BRAF^V600E–MEK1 binding and BRAF^V600E-dependent phosphorylation of MEK1 in a dose-dependent manner via direct interaction with BRAF^V600E. BRAF inhibition resulted in decreased HMGCL mRNA levels, whereas MEK1 inhibition did not, suggesting that active BRAF^V600E upregulates HMGCL independent of MEK1–ERK signaling. Consistent with this idea, active BRAF stimulated binding of the transcription factor OCT1 to the HMGCL promoter, and OCT1 knockdown resulted in decreased HMGCL expression in BRAF^V600E-mutant cells but not in BRAF wild-type cells. Taken together, these findings suggest a mutation-specific mechanism of melanoma cell proliferation by which active BRAF^V600E upregulates HMGCL via OCT1, leading to increased production of AA, which in turn promotes BRAF^V600E–MEK1 binding. These results link the ketogenic pathway to BRAF–MEK1 signaling in cancer cells and suggest that HMGCL inhibition may represent a potential alternative therapy for BRAF^V600E-positive cancers.

Kang HB, Fan J, Lin R, Elf S, Ji Q, Zhao L, et al. Metabolic rewiring by oncogenic BRAF V600E links ketogenesis pathway to BRAF-MEK1 signaling. Mol Cell 2015 Jul 2 [Epub ahead of print].