Ron kinase transphosphorylation sustains MET oncogene addiction

Receptors for the scatter factors HGF and MSP that are encoded by the MET and RON oncogenes are key players in invasive growth. Receptor crosstalk between Met and Ron occurs. Amplification of the MET oncogene results in kinase activation, deregulated expression of an invasive growth phenotype, and addiction to MET oncogene signaling (i.e. dependency on sustained Met signaling for survival and proliferation). Here we show that cancer cells addicted to MET also display constitutive activation of the Ron kinase. In human cancer cell lines co-expressing the two oncogenes, Ron is specifically trans-phosphorylated by activated Met. In contrast, Ron phosphorylation is not triggered in cells harbouring constitutively active kinase receptors other than Met, including Egfr or Her2. Further, Ron phosphorylation is suppressed by Met-specific kinase inhibitors (PHA-665752 or JNJ-38877605). Lastly, Ron phosphorylation is quenched by reducing cell surface expression of Met proteins by antibody-induced shedding. In MET addicted cancer cells, shRNA-mediated silencing of RON expression resulted in decreased proliferation and clonogenic activity in vitro and tumorigenicity in vivo. Our findings establish that oncogene addiction to MET involves Ron transactivation, pointing to Ron kinase as a target for combinatorial cancer therapy.