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The Met kinase inhibitor SU11274 exhibits a selective inhibition pattern toward different receptor mutated variants

Oncogene volume 23, pages 5387–5393 (2004)Cite this article

Abstract

Point mutations constitute a major mode of oncogenic activation of the Met receptor tyrosine kinase. Met is aberrantly activated in many types of human malignancies and its deregulated activity is correlated with aggressive tumor traits such as abnormal proliferation and survival, leading to tumor growth, local invasion and metastasis. Here we report that the Met kinase inhibitor SU11274 differentially affects the kinase activity and subsequent signaling of various mutant forms of Met. Two Met variants tested, M1268T and H1112Y, were potently inhibited by 2 μ M SU11274, while two other variants, L1213V and Y1248H, remained resistant under similar experimental conditions. Inhibition of the kinase altered cell proliferation, morphology and motility, while cells containing resistant mutants appeared unaffected by the compound. The basis for the sensitivity or resistance to SU11274 is discussed in terms of the position of the mutations predicted from a homology model.

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Abbreviations

HGF:

hepatocyte growth factor

FGFR1:

fibroblast growth factor receptor 1

PDGFR:

platelet-derived growth factor receptor

Trk:

tropomyosin receptor kinase

Ret:

rearranged during transformation

PI3K:

phosphotidylinisitol-3-OH kinase

SDS–PAGE:

sodium dodecylsulfate–polyacrylamide gel electrophoresis

FCS:

fetal calf serum

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Acknowledgements

We thank Professor Robert Friis and Dr Maria Miller for many helpful discussions. This work was funded by a Bernische Krebsliga grant to Yitzhak Zimmer and Daniel M Aebersold. In the case of Laura S Schmidt, it was funded in part with Federal funds from the NCI, NIH, under Contract No. N01-C0-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.

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Authors and Affiliations

  1. Department of Radiation Oncology, Inselspital Bern, Switzerland

    Sylvie Berthou, Daniel M Aebersold, Christine Heigl, Bruno Streit, Denise Stalder, Guenther Gruber, Richard H Greiner & Yitzhak Zimmer

  2. Department of Clinical Research, University of Bern, Murtenstrasse 35/D-809, Bern, 3010, Switzerland

    Daniel M Aebersold, Deborah Stroka & Yitzhak Zimmer

  3. Basic Research Program, SAIC-Frederick, Inc., National Cancer Institute-Frederick, Frederick, 21702, MD, USA

    Laura S Schmidt

  4. Department of Visceral Surgery, Inselspital Bern, Switzerland

    Deborah Stroka & Daniel Candinas

  5. SUGEN, Inc, South San Francisco, 94080, CA, USA

    Congxin Liang, Anthony R Howlett & Kenneth E Lipson

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  1. Sylvie Berthou
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Correspondence to Yitzhak Zimmer.

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Berthou, S., Aebersold, D., Schmidt, L. et al. The Met kinase inhibitor SU11274 exhibits a selective inhibition pattern toward different receptor mutated variants. Oncogene 23, 5387–5393 (2004). https://doi.org/10.1038/sj.onc.1207691

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  • DOI: https://doi.org/10.1038/sj.onc.1207691

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