Data from Ron Kinase Transphosphorylation Sustains <i>MET</i> Oncogene Addiction

Abstract

<div>Abstract<p>Receptors for the scatter factors <i>HGF</i> and <i>MSP</i> that are encoded by the <i>MET</i> and <i>RON</i> oncogenes are key players in invasive growth. Receptor cross-talk between Met and Ron occurs. Amplification of the <i>MET</i> oncogene results in kinase activation, deregulated expression of an <i>invasive growth</i> phenotype, and addiction to <i>MET</i> oncogene signaling (i.e., dependency on sustained Met signaling for survival and proliferation). Here we show that cancer cells addicted to <i>MET</i> also display constitutive activation of the Ron kinase. In human cancer cell lines coexpressing the 2 oncogenes, Ron is specifically transphosphorylated by activated Met. In contrast, <i>Ron</i> phosphorylation is not triggered in cells harboring constitutively active kinase receptors other than Met, including Egfr or Her2. Furthermore, Ron phosphorylation is suppressed by Met-specific kinase inhibitors (PHA-665752 or JNJ-38877605). Last, Ron phosphorylation is quenched by reducing cell surface expression of Met proteins by antibody-induced shedding. In <i>MET-</i>addicted cancer cells, short hairpin RNA–mediated silencing of <i>RON</i> expression resulted in decreased proliferation and clonogenic activity <i>in vitro</i> and tumorigenicity <i>in vivo</i>. Our findings establish that oncogene addiction to <i>MET</i> involves Ron transactivation, pointing to Ron kinase as a target for combinatorial cancer therapy. <i>Cancer Res; 71(5); 1945–55. ©2011 AACR</i>.</p></div>