Inhibiting phosphoglycerate dehydrogenase counteracts chemotherapeutic efficacy against MYCN ‐amplified neuroblastoma

Here we sought metabolic alterations specifically associated withMYCNamplification as nodes to indirectly target theMYCNoncogene. Liquid chromatography‐mass spectrometry‐based proteomics identified seven proteins consistently correlated with MYCN in proteomes from 49 neuroblastoma biopsies and 13 cell lines. Among these was phosphoglycerate dehydrogenase (PHGDH), the rate‐limiting enzyme in de novo serine synthesis. MYCN associated with two regions in thePHGDHpromoter, supporting transcriptionalPHGDHregulation by MYCN. Pulsed stable isotope‐resolved metabolomics utilizing13C‐glucose labeling demonstrated higher de novo serine synthesis inMYCN‐amplified cells compared to cells with diploidMYCN. An independence ofMYCN‐amplified cells from exogenous serine and glycine was demonstrated by serine and glycine starvation, which attenuated nucleotide pools and proliferation only in cells with diploidMYCNbut did not diminish these endpoints inMYCN‐amplified cells. Proliferation was attenuated inMYCN‐amplified cells by CRISPR/Cas9‐mediatedPHGDHknockout or treatment with PHGDH small molecule inhibitors without affecting cell viability. PHGDH inhibitors administered as single‐agent therapy to NOG mice harboring patient‐derivedMYCN‐amplified neuroblastoma xenografts slowed tumor growth. However, combining a PHGDH inhibitor with the standard‐of‐care chemotherapy drug, cisplatin, revealed antagonism of chemotherapy efficacy in vivo. Emergence of chemotherapy resistance was confirmed in the genetic PHGDH knockout model in vitro. Altogether, PHGDH knockout or inhibition by small molecules consistently slows proliferation, but stops short of killing the cells, which then establish resistance to classical chemotherapy. Although PHGDH inhibition with small molecules has produced encouraging results in other preclinical cancer models, this approach has limited attractiveness for patients with neuroblastoma.