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Updated: Sep 4, 2025

Establishment and Characterization of Three Afatinib-resistant Lung Adenocarcinoma PC-9 Cell Lines Developed with Increasing Doses of Afatinib
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Establishment and Characterization of Three Afatinib-resistant Lung Adenocarcinoma PC-9 Cell Lines Developed with Increasing Doses of Afatinib

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Activated amino acid response pathway generates apatinib resistance by reprograming glutamine metabolism in

Xiaoshu Zhou1,2, Rui Zhou1,2, Xinrui Rao1,2

  • 1Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.

Cell Death & Disease
|July 21, 2022
PubMed

Insights

Apatinib alters cancer cell metabolism by impacting glutamine processing in non-small-cell lung cancer (NSCLC). Targeting the ATF4 pathway may overcome drug resistance, enhancing apatinib

Area of Science:

  • Biochemistry
  • Oncology
  • Molecular Biology

Background:

  • Apatinib is effective against solid tumors like non-small-cell lung cancer (NSCLC).
  • Mechanisms of apatinib's tumor-killing effects and drug resistance remain unclear.
  • Understanding metabolic reprogramming is crucial for cancer therapy.

Purpose of the Study:

  • To elucidate the functional mechanisms of apatinib-induced tumor lethality in NSCLC.
  • To investigate the precise mechanisms underlying apatinib resistance.
  • To explore the role of glutamine metabolism and the amino acid response pathway.

Main Methods:

  • Investigated apatinib's effect on glutamine metabolism in human NSCLC cells.
  • Analyzed the expression of key metabolic enzymes (GLS1, SLC1A5, ASNS) and signaling pathways (GCN2/eIF2α/ATF4).
  • Utilized ATF4 silencing (knockdown) in combination with apatinib treatment in vitro and in vivo.

Main Results:

  • Apatinib repressed glutaminase 1 (GLS1) expression, disrupting glutamine catabolism.
  • This metabolic disruption activated the amino acid response (AAR) pathway via GCN2/eIF2α/ATF4.
  • Activated ATF4 induced SLC1A5 and ASNS, increasing glutamine uptake and metabolism.
  • Combined apatinib treatment and ATF4 silencing abolished glutamine metabolism and enhanced anti-tumor effects.

Conclusions:

  • Apatinib reprograms glutamine metabolism in NSCLC cells by activating the AAR pathway.
  • ATF4 plays a critical role in mediating metabolic adaptation and potential resistance to apatinib.
  • Targeting ATF4 presents a promising therapeutic strategy to overcome apatinib resistance in NSCLC.

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