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

Yanan D 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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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
Externally publishedYes

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Lung
Non-Small Cell Lung Carcinoma
Apoptosis
Endothelial Cells
Proto-Oncogene Proteins c-met
Cell Line
Proto-Oncogenes
Bronchoalveolar Lavage
Small Interfering RNA
Transfection
Cultured Cells
Carcinogenesis
Therapeutics
Cell Culture Techniques
5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one
Mutation
Neoplasms
Adenocarcinoma of lung

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology

Cite this

A selective small molecule inhibitor of c-Met, PHA-665752, reverses lung premalignancy induced by mutant K-ras. / Yang, Yanan D; Wislez, Marie; Fujimoto, Nobukazu; Prudkin, Ludmila; Izzo, Julie G.; Uno, Futoshi; Ji, Lin; Hanna, Amy E.; Langley, Robert R.; Liu, Diane; Johnson, Faye M.; Wistuba, Ignacio; Kurie, Jonathan M.

In: Molecular Cancer Therapeutics, Vol. 7, No. 4, 01.04.2008, p. 952-960.

Research output: Contribution to journalArticle

Yang, YD, Wislez, M, Fujimoto, N, Prudkin, L, Izzo, JG, Uno, F, Ji, L, Hanna, AE, Langley, RR, Liu, D, Johnson, FM, Wistuba, I & Kurie, JM 2008, 'A selective small molecule inhibitor of c-Met, PHA-665752, reverses lung premalignancy induced by mutant K-ras', Molecular Cancer Therapeutics, vol. 7, no. 4, pp. 952-960. https://doi.org/10.1158/1535-7163.MCT-07-2045
Yang, Yanan D ; Wislez, Marie ; Fujimoto, Nobukazu ; Prudkin, Ludmila ; Izzo, Julie G. ; Uno, Futoshi ; Ji, Lin ; Hanna, Amy E. ; Langley, Robert R. ; Liu, Diane ; Johnson, Faye M. ; Wistuba, Ignacio ; Kurie, Jonathan M. / A selective small molecule inhibitor of c-Met, PHA-665752, reverses lung premalignancy induced by mutant K-ras. In: Molecular Cancer Therapeutics. 2008 ; Vol. 7, No. 4. pp. 952-960.
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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.",
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AU - Izzo, Julie G.

AU - Uno, Futoshi

AU - Ji, Lin

AU - Hanna, Amy E.

AU - Langley, Robert R.

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