Franklin Chung

Oncogenic mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) occur in several types of cancer, but the metabolic consequences of these genetic changes are not fully understood. In this study, we performed (13)C metabolic flux analysis on a panel of isogenic cell lines containing heterozygous IDH1/2 mutations. We observed that under hypoxic conditions, IDH1-mutant cells exhibited increased oxidative tricarboxylic acid metabolism along with decreased reductive glutamine metabolism, but not IDH2-mutant cells. However, selective inhibition of mutant IDH1 enzyme function could not reverse the defect in reductive carboxylation activity. Furthermore, this metabolic reprogramming increased the sensitivity of IDH1-mutant cells to hypoxia or electron transport chain inhibition in vitro. Lastly, IDH1-mutant cells also grew poorly as subcutaneous xenografts within a hypoxic in vivo microenvironment. Together, our results suggest therapeutic opportunities to exploit the metabolic vulnerabilities specific to IDH1 mutation.

// Jinyun Chen 1 , Franklin Chung 1 , Guizhi Yang 1 , Minying Pu 1 , Hui Gao 1 , Wei Jiang 2 , Hong Yin 2 , Vladimir Capka 2 , Shailaja Kasibhatla 3 , Bryan Laffitte 3 , Savina Jaeger 1 , Raymond Pagliarini 1 , Yaoyu Chen 1  and Wenlai Zhou 1 1 Oncology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, United States 2 Analytic Science, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, United States 3 The Genomics Institute of the Novartis Research Foundation, San Diego, California, United States Correspondence: Yaoyu Chen, email : yaoyu.chen@novartis.com, email: // Wenlai Zhou, email: // Keywords : PHGDH, breast cancer cells, in vivo Received : October 24, 2013 Accepted : November 24, 2013 Published : November 26, 2013 Abstract Cancer cells rely on aerobic glycolysis to maintain cell growth and proliferation via the Warburg effect. Phosphoglycerate dehydrogenase (PHDGH) catalyzes the first step of the serine biosynthetic pathway downstream of glycolysis, which is a metabolic gatekeeper both for macromolecular biosynthesis and serine-dependent DNA synthesis. Here, we report that PHDGH is overexpressed in many ER-negative human breast cancer cell lines. PHGDH knockdown in these cells leads to a reduction of serine synthesis and impairment of cancer cell proliferation. However, PHGDH knockdown does not affect tumor maintenance and growth in established breast cancer xenograft models, suggesting that PHGDH-dependent cancer cell growth may be context-dependent. Our findings suggest that other mechanisms or pathways may bypass exclusive dependence on PHGDH in established human breast cancer xenografts, indicating that PHGDH is dispensable for the growth and maintenance and of tumors in vivo .