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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. | ||||||||||||
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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. |
Molecular Profile | Treatment Approach |
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Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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Merestinib | Merestinib | 0 | 4 |
Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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Merestinib | LY2801653|LY-2801653 | AXL Inhibitor 30 DDR1 Inhibitor 10 DDR2 inhibitor 7 FLT3 Inhibitor 65 MET Inhibitor 59 RON Inhibitor 11 ROS1 Inhibitor 20 Trk Receptor Inhibitor (Pan) 31 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 |
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Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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