K252a inhibits the oncogenic properties of Met, the HGF receptor.
Morotti A, Mila S, Accornero P, Tagliabue E, Ponzetto C.
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.
Publication Types:
Research Support, Non-U.S. Gov't
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