Journal
CANCER RESEARCH
Volume 67, Issue 8, Pages 3529-3534Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-06-4416
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Funding
- NCI NIH HHS [CA 125541-01, CA 100750-04] Funding Source: Medline
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The c-Met receptor tyrosine kinase is emerging as a novel target in many solid tumors, including lung cancer. PHA665752 was identified as a small molecule, ATP competitive inhibitor of the catalytic activity of the c-Met kinase. Here, we show that treatment with PHA665752 reduced NCI-H69 (small cell lung cancer) and NCI-H441 (non-small cell lung cancer) tumorigenicity in mouse xenografts by 99% and 75%, respectively. Reduction in tumor size was also observed by magnetic resonance imaging of tumors in mice. PRA665752 inhibited c-Met phosphorylation at the autophosphorylation and c-CbI binding sites in mouse xenografts derived from non-small cell lung cancer cell lines (NO-H441 and A549) and small cell lung cancer cell line (NCI-H69). PRA665752 also inhibited angiogenesis by > 85% in all the abovementioned cell lines and caused an angiogenic switch which resulted in a decreased production of vascular endothelial growth factor and an increase in the production of the angiogenesis inhibitor thrombospondin-1. These studies show the feasibility of selectively targeting c-Met with ATP competitive small molecule inhibitors and suggest that PHA665752 may provide a novel therapeutic approach to lung cancer.
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