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Blocking STAT3 by pyrvinium pamoate causes metabolic lethality in KRAS-mutant lung cancer

JuanJuan Feng1, Wenhao Jiang1, Yanan Liu1

  • 1Shanghai Key Laboratory of Regulatory Biology and School of Life Sciences, Maternity and Infant Health Hospital Affiliated to East China Normal University, Shanghai Changning Maternity and Infant Health Hospital, East China Normal Indeniversity, Shanghai 200241, China.

Biochemical Pharmacology
|April 17, 2020
PubMed

Insights

Pyrvinium pamoate inhibits Signal Transducer and Activator of Transcription 3 (STAT3) in KRAS-mutant lung cancer, causing metabolic lethality. Combining pyrvinium with glucose deprivation enhances its anti-cancer effects.

Area of Science:

  • Oncology
  • Molecular Biology
  • Metabolic Pathways

Background:

  • Signal transducer and activator of transcription 3 (STAT3) is crucial for mitochondrial function, cellular metabolism, and RAS-dependent tumor growth.
  • The therapeutic potential of STAT3 inhibition for metabolic synthetic lethality in KRAS-mutant lung cancer is not well understood.

Purpose of the Study:

  • To investigate the efficacy of pharmacological STAT3 blockade using pyrvinium pamoate in KRAS-mutant lung cancer.
  • To elucidate the underlying mechanisms of pyrvinium's anti-cancer activity and its potential for synthetic lethality.

Main Methods:

  • In vitro and in vivo studies using KRAS-mutant lung cancer cell lines and patient-derived xenografts.
  • Assessment of STAT3 phosphorylation, mitochondrial function (ROS production, membrane potential), aerobic glycolysis, and cell viability.
  • Evaluation of combined treatment effects with glucose deprivation.

Main Results:

  • Pyrvinium pamoate selectively inhibited KRAS-mutant lung cancer cell growth by suppressing STAT3 phosphorylation.
  • Targeting STAT3 with pyrvinium disrupted mitochondrial function and suppressed aerobic glycolysis.
  • Combined pyrvinium and glucose deprivation synergistically enhanced anti-cancer effects, correlating with STAT3 suppression.

Conclusions:

  • KRAS-mutant lung cancer cells exhibit vulnerability to STAT3 inhibition by pyrvinium pamoate.
  • Pyrvinium pamoate induces metabolic synthetic lethality in KRAS-mutant lung cancer, offering a potential therapeutic strategy.
  • Combined targeting of STAT3 and metabolic pathways presents a promising approach for treating KRAS-mutant lung cancer.
Keywords:
KRASMetabolismPyrvinium pamoateSTAT3Synthetic lethality

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