A selective small molecule inhibitor of c-Met, PHA665752, inhibits tumorigenicity and angiogenesis in mouse lung cancer xenografts

• Published in: Cancer research (Chicago, Ill.) Vol. 67; no. 8; pp. 3529 - 3534
• Main Authors: Puri, Neelu, Khramtsov, Andrey, Ahmed, Salman, Nallasura, Vidya, Hetzel, Jeremy T, Jagadeeswaran, Ramasamy, Karczmar, Greg, Salgia, Ravi
• Format: Journal Article
• Language: English
• Published: United States 15.04.2007
• Subjects: Animals; Carcinoma, Non-Small-Cell Lung - blood supply; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - enzymology; Carcinoma, Non-Small-Cell Lung - pathology; Carcinoma, Small Cell - blood supply; Carcinoma, Small Cell - drug therapy; Carcinoma, Small Cell - enzymology; Carcinoma, Small Cell - pathology; Cell Growth Processes - drug effects; Cell Line, Tumor; Humans; Immunohistochemistry; Indoles - pharmacology; Lung Neoplasms - blood supply; Lung Neoplasms - drug therapy; Lung Neoplasms - enzymology; Lung Neoplasms - pathology; Male; Mice; Mice, Nude; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; Proto-Oncogene Proteins c-met - antagonists & inhibitors; Sulfones - pharmacology; Thrombospondin 1 - biosynthesis; Vascular Endothelial Growth Factor A - biosynthesis; Xenograft Model Antitumor Assays
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-06-4416

The c-Met receptor tyrosine kinase is emerging as a novel target in many solid tumors, including lung cancer. PHA-665752 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. PHA665752 inhibited c-Met phosphorylation at the autophosphorylation and c-Cbl binding sites in mouse xenografts derived from non-small cell lung cancer cell lines (NCI-H441 and A549) and small cell lung cancer cell line (NCI-H69). PHA665752 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.