1. Academic Validation
  2. Serine Biosynthesis Is a Metabolic Vulnerability in IDH2-Driven Breast Cancer Progression

Serine Biosynthesis Is a Metabolic Vulnerability in IDH2-Driven Breast Cancer Progression

  • Cancer Res. 2021 Mar 15;81(6):1443-1456. doi: 10.1158/0008-5472.CAN-19-3020.
Georgina D Barnabas 1 Joo Sang Lee 2 3 Tamar Shami 4 Michal Harel 1 Lir Beck 1 Michael Selitrennik 1 Livnat Jerby-Arnon 5 Neta Erez 4 Eytan Ruppin 3 Tamar Geiger 6
Affiliations

Affiliations

  • 1 Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
  • 2 Department of Artificial Intelligence & Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon, Republic of Korea.
  • 3 Cancer Data Science Lab, CCR, NCI, NIH, Maryland.
  • 4 Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
  • 5 Department of Genetics, Stanford University School of Medicine, Stanford, California.
  • 6 Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. geiger@tauex.tau.ac.il.
Abstract

Cancer-specific metabolic phenotypes and their vulnerabilities represent a viable area of Cancer research. In this study, we explored the association of breast Cancer subtypes with different metabolic phenotypes and identified isocitrate dehydrogenase 2 (IDH2) as a key player in triple-negative breast Cancer (TNBC) and HER2. Functional assays combined with mass spectrometry-based analyses revealed the oncogenic role of IDH2 in cell proliferation, anchorage-independent growth, glycolysis, mitochondrial respiration, and antioxidant defense. Genome-scale metabolic modeling identified phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase (PSAT1) as the synthetic dosage lethal (SDL) partners of IDH2. In agreement, CRISPR-Cas9 knockout of PHGDH and PSAT1 showed the essentiality of serine biosynthesis proteins in IDH2-high cells. The clinical significance of the SDL interaction was supported by patients with IDH2-high/PHGDH-low tumors, who exhibited longer survival than patients with IDH2-high/PHGDH-high tumors. Furthermore, PHGDH inhibitors were effective in treating IDH2-high cells in vitro and in vivo. Altogether, our study creates a new link between two known Cancer regulators and emphasizes PHGDH as a promising target for TNBC with IDH2 overexpression. SIGNIFICANCE: These findings highlight the metabolic dependence of IDH2 on the serine biosynthesis pathway, adding an important layer to the connection between TCA cycle and glycolysis, which can be translated into novel targeted therapies.

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