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- Title
Identification of metabolic vulnerabilities of receptor tyrosine kinases-driven cancer.
- Authors
Jin, Nan; Bi, Aiwei; Lan, Xiaojing; Xu, Jun; Wang, Xiaomin; Liu, Yingluo; Wang, Ting; Tang, Shuai; Zeng, Hanlin; Chen, Ziqi; Tan, Minjia; Ai, Jing; Xie, Hua; Zhang, Tao; Liu, Dandan; Huang, Ruimin; Song, Yue; Leung, Elaine Lai-Han; Yao, Xiaojun; Ding, Jian
- Abstract
One of the biggest hurdles for the development of metabolism-targeted therapies is to identify the responsive tumor subsets. However, the metabolic vulnerabilities for most human cancers remain unclear. Establishing the link between metabolic signatures and the oncogenic alterations of receptor tyrosine kinases (RTK), the most well-defined cancer genotypes, may precisely direct metabolic intervention to a broad patient population. By integrating metabolomics and transcriptomics, we herein show that oncogenic RTK activation causes distinct metabolic preference. Specifically, EGFR activation branches glycolysis to the serine synthesis for nucleotide biosynthesis and redox homeostasis, whereas FGFR activation recycles lactate to fuel oxidative phosphorylation for energy generation. Genetic alterations of EGFR and FGFR stratify the responsive tumors to pharmacological inhibitors that target serine synthesis and lactate fluxes, respectively. Together, this study provides the molecular link between cancer genotypes and metabolic dependency, providing basis for patient stratification in metabolism-targeted therapies. Cancer subtypes may have distinct metabolic vulnerabilities that can be exploited for therapeutic interventions. Here, the authors show that in lung cancer, genetic activation of distinct oncogenic receptor tyrosine kinases results in unique metabolic liabilities and, in particular, EGFR aberrant cancers rely on the serine biosynthetic pathway while FGFR aberrant cancers rely on glycolysis.
- Publication
Nature Communications, 2019, Vol 10, Issue 1, pN.PAG
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-019-10427-2