This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Puri, N. Articles by Salgia, R. Search for Related Content PubMed PubMed Citation Articles by Puri, N. Articles by Salgia, R.

A Selective Small Molecule Inhibitor of c-Met, PHA665752, Inhibits Tumorigenicity and Angiogenesis in Mouse Lung Cancer Xenografts

Sections of Gastroenterology and Hematology/Oncology, Departments of Medicine, Radiology, and Pathology, University of Chicago Medical Center and University of Chicago Cancer Research Center, Chicago, Illinois

Requests for reprints: Ravi Salgia, Department of Medicine, Section of Hematology/Oncology, University of Chicago Medical Center, 5841 South Maryland Avenue, MC 2115, Chicago, IL 60607. Phone: 773-702-4399; Fax: 773-784-1798; E-mail: rsalgia{at}medicine.bsd.uchicago.edu.

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. [Cancer Res 2007;67(8):3529–34]

This article has been cited by other articles:

				S. Krishnaswamy, R. Kanteti, J. S. Duke-Cohan, S. Loganathan, W. Liu, P. C. Ma, M. Sattler, P. A. Singleton, N. Ramnath, F. Innocenti, et al. Ethnic Differences and Functional Analysis of MET Mutations in Lung Cancer Clin. Cancer Res., September 15, 2009; 15(18): 5714 - 5723. [Abstract] [Full Text] [PDF]

				T. Y. Seiwert, R. Jagadeeswaran, L. Faoro, V. Janamanchi, V. Nallasura, M. El Dinali, S. Yala, R. Kanteti, E. E.W. Cohen, M. W. Lingen, et al. The MET Receptor Tyrosine Kinase Is a Potential Novel Therapeutic Target for Head and Neck Squamous Cell Carcinoma Cancer Res., April 1, 2009; 69(7): 3021 - 3031. [Abstract] [Full Text] [PDF]

				L. Toschi and P. A. Janne Single-Agent and Combination Therapeutic Strategies to Inhibit Hepatocyte Growth Factor/MET Signaling in Cancer Clin. Cancer Res., October 1, 2008; 14(19): 5941 - 5946. [Abstract] [Full Text] [PDF]

				C. Basilico, A. Arnesano, M. Galluzzo, P. M. Comoglio, and P. Michieli A High Affinity Hepatocyte Growth Factor-binding Site in the Immunoglobulin-like Region of Met J. Biol. Chem., July 25, 2008; 283(30): 21267 - 21277. [Abstract] [Full Text] [PDF]

				Y. Yang, M. Wislez, N. Fujimoto, L. Prudkin, J. G. Izzo, F. Uno, L. Ji, A. E. Hanna, R. R. Langley, D. Liu, et al. A selective small molecule inhibitor of c-Met, PHA-665752, reverses lung premalignancy induced by mutant K-ras Mol. Cancer Ther., April 1, 2008; 7(4): 952 - 960. [Abstract] [Full Text] [PDF]

				R. Salgia c-Met Receptor Tyrosine Kinase as a Therapeutic Target in Cancer ASCO Educational Book, January 1, 2008; 2008(1): 113 - 118. [Abstract] [Full Text] [PDF]

				S. V. Sharma and J. Settleman Oncogene addiction: setting the stage for molecularly targeted cancer therapy Genes & Dev., December 15, 2007; 21(24): 3214 - 3231. [Abstract] [Full Text] [PDF]