Identification of metabolic vulnerabilities of receptor tyrosine kinases-driven cancer

Nan Jin, Aiwei Bi, Xiaojing Lan, Jun Xu, Xiaomin Wang, Yingluo Liu, Ting Wang, Shuai Tang, Hanlin Zeng, Ziqi Chen, Minjia Tan, Jing Ai, Hua Xie, Tao Zhang, Dandan Liu, Ruimin Huang, Yue Song, Elaine Lai-Han Leung, Xiaojun Yao, Jian Ding, Meiyu Geng (), Shu-Hai Lin () and Min Huang ()
Additional contact information
Nan Jin: Chinese Academy of Sciences
Aiwei Bi: Chinese Academy of Sciences
Xiaojing Lan: Chinese Academy of Sciences
Jun Xu: Chinese Academy of Sciences
Xiaomin Wang: Chinese Academy of Sciences
Yingluo Liu: Chinese Academy of Sciences
Ting Wang: Chinese Academy of Sciences
Shuai Tang: Chinese Academy of Sciences
Hanlin Zeng: Chinese Academy of Sciences
Ziqi Chen: Chinese Academy of Sciences
Minjia Tan: University of Chinese Academy of Sciences
Jing Ai: Chinese Academy of Sciences
Hua Xie: Chinese Academy of Sciences
Tao Zhang: Chinese Academy of Sciences
Dandan Liu: University of Chinese Academy of Sciences
Ruimin Huang: University of Chinese Academy of Sciences
Yue Song: Agilent Technologies (China) Co., Ltd.
Elaine Lai-Han Leung: State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology
Xiaojun Yao: State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology
Jian Ding: Chinese Academy of Sciences
Meiyu Geng: Chinese Academy of Sciences
Shu-Hai Lin: Xiamen University
Min Huang: Chinese Academy of Sciences

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10427-2

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