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Research Articles: Therapeutics, Targets, and Development

A selective small molecule inhibitor of c-Met, PHA-665752, reverses lung premalignancy induced by mutant K-ras

Departments of ¹ Thoracic/Head and Neck Medical Oncology, ² Experimental Therapeutics, ³ Thoracic and Cardiovascular Surgery, ⁴ Cancer Biology, ⁵ Biostatistics and Applied Mathematics, and ⁶ Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; and ⁷ UPRESEA3493, CHU Saint-Antoine, Université Paris-VI, Paris, France

Requests for reprints: Jonathan M. Kurie, Departments of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, 77030. Phone: 713-792-6383; Fax: 713-796-8665. E-mail: jkurie{at}mdanderson.org

Abstract

The c-Met receptor tyrosine kinase has been implicated in cellular transformation induced by mutant Ras, a commonly activated proto-oncogene in non-small cell lung cancer (NSCLC). However, the role of c-Met has not been defined in K-ras-mutant NSCLC, a disease for which no effective targeted therapeutic options currently exist. To acquire a greater understanding of its role, we used genetic and pharmacologic approaches to inhibit c-Met in mice and cultured cells. In Kras^LA1 mice, which develop premalignant lung lesions that progress to multifocal lung adenocarcinomas owing to somatic mutations in K-ras, c-Met was expressed in multiple cell types within premalignant lung lesions, and high concentrations of HGF were detected in bronchoalveolar lavage samples. Short-term treatment with PHA-665752, a c-Met inhibitor, decreased the numbers of premalignant lung lesions and induced apoptosis in tumor cells and vascular endothelial cells within lesions. In cell culture, PHA-665752 induced apoptosis of a lung adenocarcinoma cell line derived from Kras^LA1 mice (LKR-13) and a murine lung endothelial cell line (MEC). c-Met depletion by siRNA transfection induced apoptosis of MECs but not LKR-13 cells. Collectively, these findings suggest that apoptosis was an on-target effect of PHA-665752 in MECs but not in LKR-13 cells. We conclude that PHA-665752 inhibited lung tumorigenesis in Kras^LA1 mice and may provide a novel therapeutic approach to the prevention of K-ras-mutant NSCLC. [Mol Cancer Ther 2008;7(4):952–60]

Grant support: P50 CA70907 (Lung Cancer SPORE) and R01 CA117965.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁸ J. Christensen, personal communication.

Received 9/ 6/07; revised 1/10/08; accepted 1/27/08.

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