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Cell, Tumor and Stem Cell Biology

Somatic Mutations Lead to an Oncogenic Deletion of Met in Lung Cancer

Monica Kong-Beltran, Somasekar Seshagiri, Jiping Zha, Wenjing Zhu, Kaumudi Bhawe, Nerissa Mendoza, Thomas Holcomb, Kanan Pujara, Jeremy Stinson, Ling Fu, Christophe Severin, Linda Rangell, Ralph Schwall, Lukas Amler, Dineli Wickramasinghe and Robert Yauch
Monica Kong-Beltran
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Somasekar Seshagiri
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Wenjing Zhu
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Kaumudi Bhawe
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Nerissa Mendoza
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Thomas Holcomb
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Kanan Pujara
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Christophe Severin
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Linda Rangell
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Ralph Schwall
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Lukas Amler
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Dineli Wickramasinghe
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Robert Yauch
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DOI: 10.1158/0008-5472.CAN-05-2749 Published January 2006
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Abstract

Activating mutations in receptor tyrosine kinases play a critical role in oncogenesis. Despite evidence that Met kinase is deregulated in human cancer, the role of activating mutations in cancers other than renal papillary carcinoma has not been well defined. Here we report the identification of somatic intronic mutations of Met kinase that lead to an alternatively spliced transcript in lung cancer, which encodes a deletion of the juxtamembrane domain resulting in the loss of Cbl E3-ligase binding. The mutant receptor exhibits decreased ubiquitination and delayed down-regulation correlating with elevated, distinct Met expression in primary tumors harboring the deleted receptor. As a consequence, phospho-Met and downstream mitogen-activated protein kinase activation is sustained on ligand stimulation. Cells expressing the Met deletion reveal enhanced ligand-mediated proliferation and significant in vivo tumor growth. A hepatocyte growth factor competitive Met antagonist inhibits receptor activation and proliferation in tumor cells harboring the Met deletion, suggesting the important role played by ligand-dependent Met activation and the potential for anticancer therapy. These results support a critical role for Met in lung cancer and somatic mutation–driven splicing of an oncogene that leads to a different mechanism for tyrosine kinase activation through altered receptor down-regulation in human cancer. (Cancer Res 2006; 66(1): 283-9)

  • Met
  • Intronic mutations
  • Cbl
  • receptor down-regulation

Footnotes

  • Note: D. Wickramasinghe and R. Yauch contributed equally to this work.

  • Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

  • Received August 3, 2005.
  • Accepted September 28, 2005.
  • ©2006 American Association for Cancer Research.
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Cancer Research: 66 (1)
January 2006
Volume 66, Issue 1
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Somatic Mutations Lead to an Oncogenic Deletion of Met in Lung Cancer
Monica Kong-Beltran, Somasekar Seshagiri, Jiping Zha, Wenjing Zhu, Kaumudi Bhawe, Nerissa Mendoza, Thomas Holcomb, Kanan Pujara, Jeremy Stinson, Ling Fu, Christophe Severin, Linda Rangell, Ralph Schwall, Lukas Amler, Dineli Wickramasinghe and Robert Yauch
Cancer Res January 1 2006 (66) (1) 283-289; DOI: 10.1158/0008-5472.CAN-05-2749

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Somatic Mutations Lead to an Oncogenic Deletion of Met in Lung Cancer
Monica Kong-Beltran, Somasekar Seshagiri, Jiping Zha, Wenjing Zhu, Kaumudi Bhawe, Nerissa Mendoza, Thomas Holcomb, Kanan Pujara, Jeremy Stinson, Ling Fu, Christophe Severin, Linda Rangell, Ralph Schwall, Lukas Amler, Dineli Wickramasinghe and Robert Yauch
Cancer Res January 1 2006 (66) (1) 283-289; DOI: 10.1158/0008-5472.CAN-05-2749
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