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

Georgina D. Barnabas, Joo Sang Lee, Tamar Shami, Michal Harel, Lir Beck, Michael Selitrennik, Livnat Jerby-Arnon, Neta Erez, Eytan Ruppin, Tamar Geiger

פרסום מחקרי: פרסום בכתב עתמאמרביקורת עמיתים

תקציר

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

שפה מקוריתאנגלית
עמודים (מ-עד)1443-1456
מספר עמודים14
כתב עתCancer Research
כרך81
מספר גיליון6
תאריך מקוון מוקדם26 ינו׳ 2021
מזהי עצם דיגיטלי (DOIs)
סטטוס פרסוםפורסם - מרץ 2021

ASJC Scopus subject areas

  • ???subjectarea.asjc.2700.2730???
  • ???subjectarea.asjc.1300.1306???

טביעת אצבע

להלן מוצגים תחומי המחקר של הפרסום 'Serine Biosynthesis Is a Metabolic Vulnerability in IDH2-Driven Breast Cancer Progression'. יחד הם יוצרים טביעת אצבע ייחודית.

פורמט ציטוט ביבליוגרפי