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

Ganapathipillai, Suganthini S and Medová, Michaela and Aebersold, Daniel M and Manley, Paul W. and Berthou, Sylvie and Streit, Bruno and Blank-Liss, Wieslawa and Greiner, Richard H and Rothen-Rutishauser, Barbara and Zimmer, Yitzhak (2008) Coupling of mutated Met variants to DNA repair via Abl and Rad51. Cancer Research, 68 (14). pp. 5769-5777. ISSN 1538-7445

Abstract

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: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); Authors final version may be deposited on institutional website/ repository if required by institution
Keywords: DNA repair; mutations; receptor tyrosine kinase
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Date Deposited: 14 Dec 2009 13:49
Last Modified: 14 Dec 2009 13:49
URI: https://oak.novartis.com/id/eprint/1068

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