Coupling of mutated Met variants to DNA repair via Abl and Rad51.
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.
Ganapathipillai
Suganthini S
SS
Clinic for Radiation Oncology, Department of Clinical Research, University of Berne, Berne, Switzerland.
Medová
Michaela
M
Aebersold
Daniel M
DM
Manley
Paul W
PW
Berthou
Sylvie
S
Streit
Bruno
B
Blank-Liss
Wieslawa
W
Greiner
Richard H
RH
Rothen-Rutishauser
Barbara
B
Zimmer
Yitzhak
Y
D021581:Active Transport, Cell Nucleus; D000818:Animals; D052160:Benzothiazoles / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D016313:Genes, abl; D014644:Genetic Variation; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D009154:Mutation; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D051135:Rad51 Recombinase / Q000235:genetics* / Q000502:physiology; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D014050:Toluene / Q000031:analogs & derivatives / Q000378:metabolism; D014443:Tyrosine / Q000737:chemistry
C478479:((3Z)-N-(3-chlorophenyl)-3-((3,5-dimethyl-4-((4-methylpiperazin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide); D052160:Benzothiazoles; D007211:Indoles; D010879:Piperazines; D011838:Radiation-Sensitizing Agents; D013449:Sulfonamides; D014050:Toluene; D014443:Tyrosine; C121565:pifithrin; D051135:Rad51 Recombinase