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Morotti A, Mila S, Accornero P, Tagliabue E, Ponzetto C.
K252a inhibits the oncogenic properties of Met, the HGF receptor.
Oncogene. 2002 Jul 25;21(32):4885-93.
Department of Anatomy, Pharmacology and Forensic Medicine,
University of Turin, C.so Massimo d'Azeglio 52, 10126 Turin,
Italy
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.
PMID: 12118367 |
