Targeting a PHGDH metabolic vulnerability in melanoma - SUMMARY
While the last 15 years have brought remarkable clinical advances in melanoma therapy, the current standard-
of-care targeted and immune therapies have hit a ‘ceiling’ that must be overcome to further improve patient
outcomes. The identification of novel targets holds tremendous promise to devise strategies to add to our clinical
armamentarium of melanoma therapies. Cancer cells adapt their metabolism to meet the metabolic requirements
of sustained proliferation, interaction with the tumor microenvironment, and outgrowth at disseminated secondary
sites. Metabolic enzymes with key roles in cancer cells are envisioned as actionable vulnerabilities. One such
enzyme is the phosphoglycerate dehydrogenase (PHGDH), which mediates the first and rate-limiting step in the
Serine synthesis pathway. PHGDH plays an important role in melanoma formation and metastasis. Interestingly,
combining PHGDH inhibition with extracellular Serine starvation is detrimental to colon cancer cells, suggesting
that limiting Serine availability may be a strategy to target cancer cells. However, current PHGDH inhibitors are
not suitable for clinical use and may also cause systemic toxicities. Thus, alternative approaches to limit Serine
availability to target melanoma cells need to be devised. We discovered that oncogenic BRAFV600E signaling
stimulates PHGDH expression and MAPK pathway inhibition diminishes baseline and Serine starvation-induced
PHGDH levels in melanoma. Preliminary in vitro analyses showed that combining a BRAFV600E inhibitor with
extracellular Serine starvation induced melanoma cell death. We therefore hypothesize that reducing PHGDH
expression by inhibiting BRAFV600E synergizes with dietary Serine restriction to reduce melanoma growth. In this
proposal, we will first use genetic approaches to test if PHGDH depletion in established melanomas will affect
tumor growth in vivo in the absence or presence of dietary Serine restriction. Additionally, we will evaluate the
therapeutic potential of combining dietary Serine restriction with different small molecule inhibitors targeting the
BRAF/MAPK/mTOR axis, some of which are FDA-approved. Our study will preclinically assess the therapeutic
potential of a new treatment strategy of melanoma that could be rapidly translated into the clinic.
