Coupling of mutated Met variants to DNA repair via Abl and Rad51

Ganapathipillai, Suganthini S; Medová, Michaela; Aebersold, Daniel M; Manley, Paul W; Berthou, Sylvie; Streit, Bruno; Blank-Liss, Wieslawa; Greiner, Richard H; Rothen-Rutishauser, Barbara; Zimmer, Yitzhak (2008). Coupling of mutated Met variants to DNA repair via Abl and Rad51. Cancer research, 68(14), pp. 5769-77. Birmingham, Ala.: American Association for Cancer Research AACR 10.1158/0008-5472.CAN-08-1269

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Abnormal activation of DNA repair pathways by deregulated signaling of receptor tyrosine kinase systems is a compelling likelihood with significant implications in both cancer biology and treatment. Here, we show that due to a potential substrate switch, mutated variants of the receptor for hepatocyte growth factor Met, but not the wild-type form of the receptor, directly couple to the Abl tyrosine kinase and the Rad51 recombinase, two key signaling elements of homologous recombination-based DNA repair. Treatment of cells that express the mutated receptor variants with the Met inhibitor SU11274 leads, in a mutant-dependent manner, to a reduction of tyrosine phosphorylated levels of Abl and Rad51, impairs radiation-induced nuclear translocation of Rad51, and acts as a radiosensitizer together with the p53 inhibitor pifithrin-alpha by increasing cellular double-strand DNA break levels following exposure to ionizing radiation. Finally, we propose that in order to overcome a mutation-dependent resistance to SU11274, this aberrant molecular axis may alternatively be targeted with the Abl inhibitor, nilotinib.

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 04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Forschungsbereich Mu50 > Forschungsgruppe Pneumologie (Erwachsene)
UniBE Contributor:	Ganapathipillai, Suganthini, Medova, Michaela, Aebersold, Daniel Matthias, Rothen-Rutishauser, Barbara, Zimmer, Yitzhak
ISSN:	0008-5472
ISBN:	18632630
Publisher:	American Association for Cancer Research AACR
Submitter:	Factscience Import
Date Deposited:	04 Oct 2013 15:03
Last Modified:	02 Mar 2023 23:22
Publisher DOI:	10.1158/0008-5472.CAN-08-1269
PubMed ID:	18632630
Web of Science ID:	000257768300034
URI:	https://boris.unibe.ch/id/eprint/27560 (FactScience: 108829)