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Coupling of Mutated Met Variants to DNA Repair via Abl and Rad51

¹ Clinic for Radiation Oncology and Department of Clinical Research, ² Institute for Anatomy, University of Berne, Berne, Switzerland; and ³ Novartis Institutes for Biomedical Research, Basel, Switzerland

Requests for reprints: Yitzhak Zimmer, Department of Clinical Research, University of Berne, Murtenstrasse 35/E-807, 3010 Berne, Switzerland. Phone: 41-31632-2642; Fax: 41-31632-3297; E-mail: yitzhak.zimmer{at}insel.ch.

Key Words: DNA repair • mutations • receptor tyrosine kinase

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- 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. [Cancer Res 2008;68(14):5769–77]

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