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 potent MET/RON dual kinase inhibitor 
LY2801653 in this setting. LY2801653 was more efficacious than the 
MET/ALK/RON/ROS inhibitor crizotinib with a distinct pattern of downstream 
signaling effects. Using the PamGene platform, we found that inhibition of MET 
and RON was associated with decreased phosphorylation of CBL, PI3K, and STAT3. 
In classic and orthotopic mouse xenograft models of lung cancer, LY2801653 
decreased tumor growth, dramatically inhibiting mitotic events and angiogenesis. 
Taken together, our results argued that specific targeting of the MET/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.