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K252a inhibits the oncogenic properties of Met, the HGF receptor

Oncogene volume 21, pages 4885–4893 (2002)Cite this article

Abstract

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.

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Acknowledgements

We thank Sylvie Ménard for help with the experimental metastasis assay. This work was supported by a grant of the Italian Association for Cancer Research (AIRC) and by funds of the CNR Progetto Finalizzato Biotecnologie. The continuing support of the Compagnia di San Paolo and Fondazione CRT to C Ponzetto's laboratory is gratefully acknowledged.

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  1. Department of Anatomy, Pharmacology and Forensic Medicine, University of Turin, C.so Massimo d'Azeglio 52, Turin, 10126, Italy

    Alessandro Morotti, Silvia Mila, Paolo Accornero & Carola Ponzetto

  2. Istituto Nazionale Tumori, Via Venezian 1, Milan, 20133, Italy

    Emma Tagliabue

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  1. Alessandro Morotti
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  2. Silvia Mila
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Correspondence to Carola Ponzetto.

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Morotti, A., Mila, S., Accornero, P. et al. K252a inhibits the oncogenic properties of Met, the HGF receptor. Oncogene 21, 4885–4893 (2002). https://doi.org/10.1038/sj.onc.1205622

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