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Updated: Nov 11, 2025

Methods for Evaluating the Role of c-Fos and Dusp1 in Oncogene Dependence
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Paradoxical activation of c-Src as a drug-resistant mechanism

Makio Higuchi1, Kenichi Ishiyama2, Masahiro Maruoka3

  • 1Department of Pharmacology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Cell Reports
|March 24, 2021
PubMed

Insights

Kinase inhibitors targeting cancer can paradoxically increase cell growth by activating c-Src and FAK signaling pathways. This discovery offers insights into overcoming drug resistance and developing safer cancer treatments.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • ATP-competitive inhibitors are crucial anti-cancer agents.
  • Drug resistance and its mechanisms remain significant challenges in cancer therapy.

Purpose of the Study:

  • To investigate the paradoxical activation of c-Src and downstream signaling by kinase inhibitors.
  • To elucidate the mechanisms underlying drug resistance to Src-targeted therapies.

Main Methods:

  • Utilized Src-targeted and RTK-targeted kinase inhibitors.
  • Analyzed conformational changes in c-Src upon inhibitor binding.
  • Investigated the association and dissociation dynamics of c-Src and FAK.
  • Examined the role of a drug-resistant c-Src mutation.

Main Results:

  • Inhibitor binding paradoxically activates c-Src and its downstream phosphorylation cascade.
  • Inhibitor dissociation enables c-Src to phosphorylate FAK, activating Erk signaling.
  • A drug-resistant c-Src mutation enhances FAK and Erk phosphorylation, promoting cell proliferation.

Conclusions:

  • Target-based kinase inhibitors can paradoxically enhance cancer cell growth.
  • Understanding these mechanisms is vital for developing effective and safe cancer treatments.
  • Findings provide crucial insights into overcoming kinase inhibitor resistance.
Keywords:
FAKallosteric effectsanchorage-dependent signalingc-Srcdrug resistancekinase inhibitorparadoxical activation

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