2. Academic Validation
  3. Identification of metabolic vulnerabilities of receptor tyrosine kinases-driven cancer

Identification of metabolic vulnerabilities of receptor tyrosine kinases-driven cancer

  • Nat Commun. 2019 Jun 20;10(1):2701. doi: 10.1038/s41467-019-10427-2.
Nan Jin 1 2,  Aiwei Bi 1 2,  Xiaojing Lan 1,  Jun Xu 1 2,  Xiaomin Wang 1 2,  Yingluo Liu 1 2,  Ting Wang 1 2,  Shuai Tang 1,  Hanlin Zeng 1 2,  Ziqi Chen 1 2,  Minjia Tan 2 3,  Jing Ai 1 2,  Hua Xie 1 2,  Tao Zhang 1 2,  Dandan Liu 2 4,  Ruimin Huang 2 4,  Yue Song 5,  Elaine Lai-Han Leung 6,  Xiaojun Yao 6,  Jian Ding 1 2,  Meiyu Geng 7 8,  Shu-Hai Lin 9,  Min Huang 10 11
Affiliations

Affiliations

  • 1 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, 201203, Shanghai, China.
  • 2 University of Chinese Academy of Sciences, No.19 Yuquan Road, 100049, Beijing, China.
  • 3 Chemical Proteomics Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, 201203, Shanghai, China.
  • 4 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, 201203, Shanghai, China.
  • 5 Agilent Technologies (China) Co., Ltd., 1350 North Sichuan Road, 200080, Shanghai, China.
  • 6 Macau Institute for Applied Research in Medicine and Health, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, 999078, Macau, China.
  • 7 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, 201203, Shanghai, China. mygeng@simm.ac.cn.
  • 8 University of Chinese Academy of Sciences, No.19 Yuquan Road, 100049, Beijing, China. mygeng@simm.ac.cn.
  • 9 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, 4221 South Xiang'an Road, 361102, Xiamen, China. shuhai@xmu.edu.cn.
  • 10 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, 201203, Shanghai, China. mhuang@simm.ac.cn.
  • 11 University of Chinese Academy of Sciences, No.19 Yuquan Road, 100049, Beijing, China. mhuang@simm.ac.cn.
PMID: 31221965 DOI: 10.1038/s41467-019-10427-2
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.

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