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Ref Type Journal Article
PMID (24305878)
Authors Kawada I, Hasina R, Arif Q, Mueller J, Smithberger E, Husain AN, Vokes EE, Salgia R
Title Dramatic antitumor effects of the dual MET/RON small-molecule inhibitor LY2801653 in non-small cell lung cancer.
Journal Cancer research
Vol 74
Issue 3
Date 2014 Feb 1
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Merestinib LY2801653|LY-2801653 AXL Inhibitor 27 DDR1 Inhibitor 8 DDR2 inhibitor 7 FLT3 Inhibitor 55 MET Inhibitor 51 RON Inhibitor 10 ROS1 Inhibitor 14 Trk Receptor Inhibitor (Pan) 23 TYRO3 Inhibitor 8 Merestinib (LY2801653) inhibits several receptor tyrosine kinases including MET, MST1R (RON), AXL, MERTK, TYRO3, ROS1 fusions, PDGFRA, FLT3, TEK, DDR1/2, MKNK1/2, and NTRK1/2/3 with greatest activity against NTRK1, and may result in decreased tumor growth (PMID: 23275061, PMID: 24305878, PMID: 29568395, PMID: 32537847).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown lung non-small cell carcinoma not applicable Merestinib Preclinical Actionable In a preclinical study, LY2801653 inhibited tumor growth in mouse xenograft models of non-small cell lung cancer (PMID: 24305878). 24305878