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Inhibiting Eph kinase activity may not be "Eph"ective for cancer treatment

A C Herington1, I Mertens-Walker, J E Lisle

  • 1Institute of Health and Biomedical Innovation, Queensland University of Technology , Queensland , Australia and.

Growth Factors (Chur, Switzerland)
|November 22, 2014
PubMed

Insights

Over-expressed Eph receptor tyrosine kinases (RTKs) drive cancer. Leaky kinase inhibitors can paradoxically promote resistance by activating Eph signaling, suggesting combination therapies for better outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Eph receptor tyrosine kinases (RTKs) are frequently over-expressed in cancers.
  • While normally tumor-suppressive, Eph over-expression can activate oncogenic signaling pathways.
  • Resistance to single-agent kinase inhibitors is a significant clinical challenge.

Purpose of the Study:

  • To investigate the role of Eph signaling in acquired resistance to kinase inhibitors.
  • To explore the impact of off-target inhibition of Ephs by non-specific kinase inhibitors.
  • To propose novel therapeutic strategies combining specific inhibitors with Eph signaling modulators.

Main Methods:

  • Review of existing literature on Eph RTKs, kinase inhibitors, and cancer resistance mechanisms.
  • Analysis of proposed off-target effects of kinase inhibitors on Eph signaling.
  • Conceptualization of combination therapy approaches.

Main Results:

  • Over-expressed Ephs can activate ligand- and/or kinase-independent oncogenic pathways.
  • Leaky kinase inhibitors targeting other RTKs may inadvertently promote Eph-driven oncogenesis.
  • This off-target effect represents a novel mechanism of resistance to RTK inhibitors.

Conclusions:

  • Targeting Eph RTKs is crucial in cancer therapy.
  • Non-specific kinase inhibitors can lead to acquired resistance through unintended Eph activation.
  • Combining specific, non-leaky kinase inhibitors with tumor-suppressive Eph signaling stimulators may overcome resistance and improve treatment efficacy.
Keywords:
Cancer resistanceEph receptorskinase inhibitors

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