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Nat Commun. 2019 Jun 20;10(1):2701. doi: 10.1038/s41467-019-10427-2.

Identification of metabolic vulnerabilities of receptor tyrosine kinases-driven cancer.

Jin N1,2, Bi A1,2, Lan X1, Xu J1,2, Wang X1,2, Liu Y1,2, Wang T1,2, Tang S1, Zeng H1,2, Chen Z1,2, Tan M2,3, Ai J1,2, Xie H1,2, Zhang T1,2, Liu D2,4, Huang R2,4, Song Y5, Leung EL6, Yao X6, Ding J1,2, Geng M7,8, Lin SH9, Huang M10,11.

Author information

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.

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.

PMID:
31221965
PMCID:
PMC6586626
DOI:
10.1038/s41467-019-10427-2
[Indexed for MEDLINE]
Free PMC Article

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