MAPK-mediated PHGDH induction is essential for melanoma formation and represents an actionable vulnerability.

ABSTRACT: Overexpression of PHGDH, the rate-limiting enzyme in the serine synthesis pathway, promotes melanomagenesis, melanoma cell proliferation, and survival of metastases in serine-low environments such as the brain. While PHGDH amplification explains PHGDH overexpression in a subset of melanomas, we find that PHGDH levels are universally increased in melanoma cells due to oncogenic BRAF^V600E promoting PHGDH transcription through mTORC1-mediated translation of ATF4. Importantly, PHGDH expression was critical for melanomagenesis as depletion of PHGDH in genetic mouse models blocked melanoma formation. Despite BRAF^V600E-mediated upregulation, PHGDH was further induced by exogenous serine restriction. Surprisingly, BRAF^V600E inhibition diminishe

SUBMITTER: Jasani N 

PROVIDER: S-EPMC11042198 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature