MET inhibition in tumor cells by PHA665752 impairs homologous recombination repair of DNA double strand breaks

Medová, Michaela; Aebersold, Daniel M; Zimmer, Yitzhak (2012). MET inhibition in tumor cells by PHA665752 impairs homologous recombination repair of DNA double strand breaks. International journal of cancer, 130(3), pp. 728-34. Malden, Mass.: Wiley-Blackwell 10.1002/ijc.26058

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Abnormal activation of cellular DNA repair pathways by deregulated signaling of receptor tyrosine kinase systems has broad implications for both cancer biology and treatment. Recent studies suggest a potential link between DNA repair and aberrant activation of the hepatocyte growth factor receptor Mesenchymal-Epithelial Transition (MET), an oncogene that is overexpressed in numerous types of human tumors and considered a prime target in clinical oncology. Using the homologous recombination (HR) direct-repeat direct-repeat green fluorescent protein ((DR)-GFP) system, we show that MET inhibition in tumor cells with deregulated MET activity by the small molecule PHA665752 significantly impairs in a dose-dependent manner HR. Using cells that express MET-mutated variants that respond differentially to PHA665752, we confirm that the observed HR inhibition is indeed MET-dependent. Furthermore, our data also suggest that decline in HR-dependent DNA repair activity is not a secondary effect due to cell cycle alterations caused by PHA665752. Mechanistically, we show that MET inhibition affects the formation of the RAD51-BRCA2 complex, which is crucial for error-free HR repair of double strand DNA lesions, presumably via downregulation and impaired translocation of RAD51 into the nucleus. Taken together, these findings assist to further support the role of MET in the cellular DNA damage response and highlight the potential future benefit of MET inhibitors for the sensitization of tumor cells to DNA damaging agents.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Radiation Oncology

UniBE Contributor:

Medova, Michaela; Aebersold, Daniel and Zimmer, Yitzhak

ISSN:

0020-7136

Publisher:

Wiley-Blackwell

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:09

Last Modified:

06 Dec 2013 13:20

Publisher DOI:

10.1002/ijc.26058

PubMed ID:

21400509

Web of Science ID:

000298602500025

URI:

https://boris.unibe.ch/id/eprint/1049 (FactScience: 201767)

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