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Ron kinase transphosphorylation sustains MET oncogene addiction
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
Summary
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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