TY - JOUR
T1 - Serine Biosynthesis Is a Metabolic Vulnerability in IDH2-Driven Breast Cancer Progression
AU - Barnabas, Georgina D.
AU - Lee, Joo Sang
AU - Shami, Tamar
AU - Harel, Michal
AU - Beck, Lir
AU - Selitrennik, Michael
AU - Jerby-Arnon, Livnat
AU - Erez, Neta
AU - Ruppin, Eytan
AU - Geiger, Tamar
N1 - Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/3
Y1 - 2021/3
N2 - 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/PHGDHlow 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
AB - 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/PHGDHlow 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
UR - http://www.scopus.com/inward/record.url?scp=85103752871&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-19-3020
DO - 10.1158/0008-5472.CAN-19-3020
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
C2 - 33500247
SN - 0008-5472
VL - 81
SP - 1443
EP - 1456
JO - Cancer Research
JF - Cancer Research
IS - 6
ER -
