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

Yanan Yang, Marie Wislez, Nobukazu Fujimoto, Ludmila Prudkin, Julie G. Izzo, Futoshi Uno, Lin Ji, Amy E. Hanna, Robert R. Langley, Diane Liu, Faye M. Johnson, Ignacio Wistuba, Jonathan M. Kurie

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61 Scopus citations

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 KrasLA1 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 KrasLA1 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 KrasLA1 mice and may provide a novel therapeutic approach to the prevention of K-ras-mutant NSCLC.

Original languageEnglish (US)
Pages (from-to)952-960
Number of pages9
JournalMolecular cancer therapeutics
Volume7
Issue number4
DOIs
StatePublished - Apr 1 2008

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Yang, Y., Wislez, M., Fujimoto, N., Prudkin, L., Izzo, J. G., Uno, F., Ji, L., Hanna, A. E., Langley, R. R., Liu, D., Johnson, F. M., Wistuba, I., & Kurie, J. M. (2008). A selective small molecule inhibitor of c-Met, PHA-665752, reverses lung premalignancy induced by mutant K-ras. Molecular cancer therapeutics, 7(4), 952-960. https://doi.org/10.1158/1535-7163.MCT-07-2045