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| Item Type: | Article |
|---|---|
| Title: | Inhibiting phosphoglycerate dehydrogenase counteracts chemotherapeutic efficacy against MYCN-amplified neuroblastoma |
| Creators Name: | Arlt, B. and Zasada, C. and Baum, K. and Wuenschel, J. and Mastrobuoni, G. and Lodrini, M. and Astrahantseff, K. and Winkler, A. and Schulte, J.H. and Finkler, S. and Forbes, M. and Hundsdoerfer, P. and Guergen, D. and Hoffmann, J. and Wolf, J. and Eggert, A. and Kempa, S. and Deubzer, H.E. |
| Abstract: | Here we sought metabolic alterations specifically associated with MYCN amplification as nodes to indirectly target the MYCN oncogene. Liquid chromatography-mass spectrometry-based proteomics identified 7 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 the PHGDH promoter, supporting transcriptional PHGDH regulation by MYCN. Pulsed stable isotope-resolved metabolomics utilizing (13)C-glucose labeling demonstrated higher de novo serine synthesis in MYCN-amplified cells compared to cells with diploid MYCN. An independence of MYCN-amplified cells from exogenous serine and glycine was demonstrated by serine and glycine starvation, which attenuated nucleotide pools and proliferation only in cells with diploid MYCN but did not diminish these endpoints in MYCN-amplified cells. Proliferation was attenuated in MYCN-amplified cells by CRISPR/Cas9-mediated PHGDH knockout or treatment with PHGDH small molecule inhibitors without affecting cell viability. PHGDH inhibitors administered as single-agent therapy to NOG mice harboring patient-derived MYCN-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. |
| Keywords: | Cancer Cell Metabolism, De Novo Serine Synthesis Pathway, One-Carbon Metabolism, Cell Death, Therapy Resistance, Animals, Mice |
| Source: | International Journal of Cancer |
| ISSN: | 0020-7136 |
| Publisher: | Wiley |
| Volume: | 148 |
| Number: | 5 |
| Page Range: | 1219-1232 |
| Date: | 1 March 2021 |
| Official Publication: | https://doi.org/10.1002/ijc.33423 |
| PubMed: | View item in PubMed |
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