Metabolic stress regulates ERK activity by controlling KSR‐RAF heterodimerization

Altered cell metabolism is a hallmark of cancer, and targeting specific metabolic nodes is considered an attractive strategy for cancer therapy. In this study, we evaluate the effects of metabolic stressors on the deregulated ERK pathway in melanoma cells bearing activating mutations of the NRAS or BRAF oncogenes. We report that metabolic stressors promote the dimerization of KSR proteins with CRAF in NRAS‐mutant cells, and with oncogenic BRAF in BRAF V600E ‐mutant cells, thereby enhancing ERK pathway activation. Despite this similarity, the two genomic subtypes react differently when a higher level of metabolic stress is induced. In NRAS‐mutant cells, the ERK pathway is even more stimulated, while it is strongly downregulated in BRAF V600E ‐mutant cells. We demonstrate that this is caused by the dissociation of mutant BRAF from KSR and is mediated by activated AMPK. Both types of ERK regulation nevertheless lead to cell cycle arrest. Besides studying the effects of the metabolic stressors on ERK pathway activity, we also present data suggesting that for efficient therapies of both genomic melanoma subtypes, specific metabolic targeting is necessary. Synopsis Somatic RAF/RAS mutations result in deregulated ERK signaling in melanomas. Metabolic stress impacts differently on ERK activation in BRAF‐ and NRAS‐mutant cells, indicating that targeting of energy metabolism is not a general therapeutic strategy for melanoma. Metabolic stress induces CRAF/KSR dimerization in NRAS‐mutant cells, increasing ERK activity. Metabolically stressed BRAF V600E ‐mutant cells show an interaction of KSR with oncogenic BRAF. High metabolic stress leads to the dissociation of mutant BRAF from KSR, reducing ERK activity. Successful metabolic targeting strategies depend on the RAS/RAF mutational status. Graphical Abstract Somatic RAF/RAS mutations result in deregulated ERK signaling in melanomas. Metabolic stress impacts differently on ERK activation in BRAF‐ and NRAS‐mutant cells, indicating that targeting of energy metabolism is not a general therapeutic strategy for melanoma.