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Updated: Oct 8, 2025

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
10:33

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

Published on: October 26, 2015

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GCN2 kinase activation by ATP-competitive kinase inhibitors

Colin P Tang1,2,3, Owen Clark1, John R Ferrarone4

  • 1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Nature Chemical Biology
|December 24, 2021
PubMed

Insights

General control nonderepressible 2 (GCN2) kinase influences cancer drug response. Discovering its role in neratinib resistance reveals new therapeutic strategies for glioblastoma and other cancers.

Area of Science:

  • Molecular Biology
  • Cancer Therapeutics
  • Genomics

Background:

  • Small-molecule kinase inhibitors are crucial cancer drugs, but incomplete tumor responses limit their efficacy.
  • Understanding mechanisms of drug resistance is vital for improving cancer treatment outcomes.

Purpose of the Study:

  • To identify cellular pathways that modulate the response to the pan-ErbB inhibitor neratinib in glioblastoma.
  • To investigate the role of the integrated stress response (ISR) in kinase inhibitor drug action.

Main Methods:

  • Conducted a genome-wide knockout (KO) screen in glioblastoma cells.
  • Treated cells with the pan-ErbB inhibitor neratinib.
  • Assessed the impact of gene knockouts on drug sensitivity and identified key regulatory proteins.

Main Results:

  • Loss of general control nonderepressible 2 (GCN2) kinase conferred resistance to neratinib.
  • Depletion of GADD34 phosphatase enhanced neratinib sensitivity.
  • GCN2 was found to directly bind and be activated by neratinib and other FDA-approved kinase inhibitors (e.g., erlotinib, sunitinib).

Conclusions:

  • The integrated stress response (ISR) pathway, particularly GCN2, plays a significant role in modulating responses to kinase inhibitors.
  • Genome-wide screens are effective for uncovering novel mechanisms of drug action and resistance.
  • Targeting the ISR may offer new strategies to overcome resistance to kinase inhibitors in cancer therapy.

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