Ron kinase transphosphorylation sustains MET oncogene addiction

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Silvia Benvenuti1, Luca Lazzari, Addolorata Arnesano

  • 1Exploratory Research Laboratory, Institute for Cancer Research and Treatment (IRCC), University of Turin Medical School, 10060 Candiolo, Turin, Italy.

Cancer Research
|January 8, 2011
PubMed

Insights

Cancer cells addicted to MET signaling also activate the RON kinase through cross-talk. Targeting RON kinase offers a new strategy for treating MET-addicted cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • The MET and RON oncogenes encode receptors crucial for invasive growth.
  • Receptor cross-talk between Met and Ron is observed in cancer.
  • MET oncogene amplification leads to invasive phenotypes and addiction to MET signaling.

Purpose of the Study:

  • To investigate the relationship between MET oncogene addiction and RON kinase activation.
  • To determine if Met signaling directly influences Ron kinase activity.
  • To explore the therapeutic potential of targeting Ron kinase in MET-addicted cancers.

Main Methods:

  • Analysis of human cancer cell lines coexpressing MET and RON.
  • Assessment of Ron kinase phosphorylation in response to Met activation.
  • Use of Met-specific kinase inhibitors (PHA-665752, JNJ-38877605).
  • Evaluation of Ron kinase activity following antibody-induced Met shedding.
  • Silencing of RON expression using short hairpin RNA (shRNA).

Main Results:

  • Cancer cells addicted to MET signaling exhibit constitutive Ron kinase activation.
  • Activated Met specifically transphosphorylates Ron kinase.
  • Ron phosphorylation is inhibited by Met-specific kinase inhibitors and Met shedding.
  • RON silencing reduces proliferation, clonogenic activity, and tumorigenicity in MET-addicted cells.

Conclusions:

  • Oncogene addiction to MET involves Ron kinase transactivation.
  • Ron kinase is a potential therapeutic target for combinatorial cancer therapy in MET-addicted cancers.

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