K252a inhibits the oncogenic properties of Met, the HGF receptor.
The ATP analog K252a is a potent inhibitor for receptor tyrosine kinases of the Trk family. Here we show that nanomolar concentrations of K252a prevent HGF-mediated scattering in MLP-29 cells (30 nM), reduce Met-driven proliferation in GTL-16 gastric carcinoma cells (100 nM), and cause reversion in NIH3T3 fibroblasts transformed by the oncogenic form of the receptor, Tpr-Met (75 nM). K252a inhibits Met autophosphorylation in cultured cells and in immunoprecipitates and prevents activation of its downstream effectors MAPKinase and Akt. Interestingly, K252a seems to be more effective at inhibiting the mutated form of Met (M1268T) found in papillary carcinoma of the kidney than the wild type receptor. Pretreatment of both Tpr-Met-transformed NIH3T3 fibroblasts and of GTL-16 gastric carcinoma cells with K252a results in loss of their ability to form lung metastases in nude mice upon injection into the caudal vein. These observations suggest that K252a derivatives, which are active in vivo as anti-cancer drugs in models of Trk-driven malignancies, should also be effective for treatment of Met-mediated tumors.
Department of Anatomy, Pharmacology and Forensic Medicine, University of Turin, C.so Massimo d'Azeglio 52, 10126 Turin, Italy.
Alessandro
A
Morotti
Silvia
S
Mila
Paolo
P
Accornero
Emma
E
Tagliabue
Carola
C
Ponzetto
D016475:3T3 Cells; D000818:Animals; D002227:Carbazoles / Q000494:pharmacology*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D026121:Indole Alkaloids; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D051379:Mice; D009374:Neoplasms, Experimental / Q000517:prevention & control; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D002227:Carbazoles; D004791:Enzyme Inhibitors; D026121:Indole Alkaloids; C049985:staurosporine aglycone; D019859:Proto-Oncogene Proteins c-met; D011493:Protein Kinase C