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A subset of VEGFR-TKIs activates AMPK in LKB1-mutant lung cancer

Lujie Yang1, Qin Zhang1, Yanli Xiong1

  • 1Cancer Center, Daping Hospital, Army Medical University, Chongqing, China.

Cancer Science
|December 2, 2022
PubMed

Insights

Apatinib activates AMP-activated protein kinase (AMPK), inhibiting fatty acid synthesis in LKB1-mutant non-small cell lung cancer (NSCLC). This discovery offers new therapeutic strategies for this aggressive cancer subset.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Liver kinase B1 (LKB1) mutations occur in ~20% of non-small cell lung cancer (NSCLC), leading to aggressive disease and poor prognosis.
  • LKB1-mutant NSCLC exhibits increased aggressiveness and immune escape, necessitating novel therapeutic approaches.
  • Apatinib, a vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI), shows promise in improving outcomes for LKB1-mutant NSCLC, but its mechanism remains unclear.

Purpose of the Study:

  • To investigate the mechanism by which apatinib improves outcomes in LKB1-mutant NSCLC.
  • To identify AMP-activated protein kinase (AMPK) as a potential off-target of apatinib.
  • To elucidate the differential effects of VEGFR-TKIs on AMPK activity and their therapeutic implications.

Main Methods:

  • Biochemical experiments to assess apatinib's direct effect on AMPK.
  • Analysis of the impact of various clinically available VEGFR-TKIs on AMPK activity.
  • Investigation of the downstream effects of AMPK activation, including acetyl-CoA carboxylase (ACC) phosphorylation and fatty acid synthesis (FAsyn) inhibition.
  • Evaluation of apatinib's efficacy under conditions of fatty acid restriction.

Main Results:

  • Biochemical assays confirmed apatinib as a direct activator of AMPK.
  • Different VEGFR-TKIs exhibited varied effects on AMPK: apatinib and anlotinib activated AMPK, while axitinib and sunitinib inhibited it.
  • Apatinib-induced AMPK activation led to ACC phosphorylation and suppressed de novo fatty acid synthesis, which is elevated in LKB1-null cancers.
  • Apatinib's anti-cancer effect was significantly enhanced by delipidated conditions, suggesting a role for fatty acid synthesis inhibition.

Conclusions:

  • AMPK is identified as a key off-target of apatinib, mediating its therapeutic effects in LKB1-mutant NSCLC.
  • VEGFR-TKIs demonstrate distinct modulation of AMPK, providing a basis for rational drug combination and application.
  • Combining apatinib with exogenous fatty acid restriction presents a promising therapeutic strategy for LKB1-mutant NSCLC.
Keywords:
AMPKSTK11VEGFR-TKIfatty acid metabolismlung cancer

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