Lung cancer is a heterogeneous disease encompassing a wide array of genetic abnormalities. The MET receptor tyrosine kinase is altered in many lung cancers, especially non-small cell lung cancer (NSCLC), and clinical trials of MET inhibitors that are under way are documenting cases of acquired resistance. On the basis of the evidence that the RON tyrosine kinase receptor can also be overexpressed in NSCLC, we evaluated the potentMET/ RONdual kinase inhibitor LY2801653 in this setting. LY2801653 wasmore efficacious than theMET/ALK/RON/ROS inhibitor crizotinib with a distinct pattern of downstreamsignaling effects. Using the PamGene platform, we found that inhibition ofMET andRONwas associated with decreased phosphorylation of CBL, PI3K, and STAT3. In classic and orthotopicmouse xenograftmodels of lung cancer, LY2801653 decreased tumor growth, dramatically inhibiting mitotic events and angiogenesis. Taken together, our results argued that specific targeting of theMET/RON kinases could provide robust inhibition of cell proliferation and tumor outgrowth in multiple in vitro and in vivo models of NSCLC. These findings offer a robust preclinical proof of concept for MET/RON targeting by LY2801653 as a promising small-molecule modality to treat NSCLC.
ASJC Scopus subject areas
- Cancer Research