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Branched-Chain Amino Acid Metabolic Reprogramming Orchestrates Drug Resistance to EGFR Tyrosine Kinase Inhibitors

Yuetong Wang1, Jian Zhang1, Shengxiang Ren2

  • 1State Key Laboratory of Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; CAS Center for Excellence in Molecular Cell Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China.

Cell Reports
|July 11, 2019
PubMed

Insights

Sublethal cancer drug treatment induces a drug-tolerant state in EGFR-mutant lung cancer cells. This tolerance is mediated by BCAT1, a metabolic enzyme, leading to drug resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Drug resistance remains a major challenge in cancer therapy.
  • Mechanisms of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in EGFR-mutant cancers are well-studied.
  • Adaptive responses to sublethal drug exposure are less understood.

Purpose of the Study:

  • To investigate how cancer cells adapt to sublethal drug challenges.
  • To elucidate the mechanisms underlying the development of TKI resistance in EGFR-mutant lung cancer.
  • To identify potential therapeutic strategies to overcome TKI resistance.

Main Methods:

  • Exposure of EGFR-mutant lung cancer cells to sublethal TKI treatment.
  • Analysis of cellular adaptive responses and development of drug tolerance.
  • Investigation of the role of H3K9 demethylation and BCAT1 expression.
  • Metabolic profiling and assessment of reactive oxygen species (ROS) levels.
  • Preclinical mouse models for combination therapy evaluation.
  • Clinical data analysis correlating BCAT1 expression with TKI response.

Main Results:

  • Sublethal TKI treatment induces a transient drug-tolerant state in EGFR-mutant lung cancer cells.
  • Continuous sublethal treatment leads to long-term TKI resistance.
  • This resistance is mediated by H3K9 demethylation-induced upregulation of BCAT1 and metabolic reprogramming.
  • BCAT1 attenuates ROS accumulation, promoting TKI resistance.
  • Combination therapy with TKI and ROS-inducing agents overcomes resistance in preclinical models.
  • BCAT1 expression correlates with EGFR TKI response in clinical data.

Conclusions:

  • BCAT1-engaged metabolic reprogramming is crucial for TKI resistance in lung cancer.
  • Targeting BCAT1 or modulating ROS levels may offer strategies to overcome EGFR TKI resistance.
  • Understanding adaptive responses to sublethal drug concentrations is vital for improving cancer treatment outcomes.
Keywords:
BCAT1EGFR tyrosine kinase inhibitorsbranched-chain amino acidsdrug resistancelung cancermetabolic reprogramming

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