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Analysis of the tyrosine kinome in melanoma reveals recurrent mutations in ERBB4

Nature Genetics volume 41, pages 1127–1132 (2009)Cite this article

Abstract

Tyrosine phosphorylation is important in signaling pathways underlying tumorigenesis. We performed a mutational analysis of the protein tyrosine kinase (PTK) gene family in cutaneous metastatic melanoma. We identified 30 somatic mutations affecting the kinase domains of 19 PTKs and subsequently evaluated the entire coding regions of the genes encoding these 19 PTKs for somatic mutations in 79 melanoma samples. We found ERBB4 mutations in 19% of individuals with melanoma and found mutations in two other kinases (FLT1 and PTK2B) in 10% of individuals with melanomas. We examined seven missense mutations in the most commonly altered PTK gene, ERBB4, and found that they resulted in increased kinase activity and transformation ability. Melanoma cells expressing mutant ERBB4 had reduced cell growth after shRNA-mediated knockdown of ERBB4 or treatment with the ERBB inhibitor lapatinib. These studies could lead to personalized therapeutics specifically targeting the kinases that are mutationally altered in individual melanomas.

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Figure 1: Distribution of mutations in ERBB4.
Figure 2: ERBB4 mutants show increased basal activation.
Figure 3: Mutant ERBB4 induces cell transformation and anchorage-independent growth in NIH 3T3 and SK-Mel-2 cells.
Figure 4: Expression of mutant ERBB4 provides an essential cell survival signal in melanoma.
Figure 5: Melanoma lines expressing ERBB4 mutants show increased sensitivity to inhibition of ERBB by lapatinib.

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Acknowledgements

We thank B. Vogelstein, T. Waldman, D. Bell, P. Meltzer, L. Brody, G. Merlino, S. Gutkind and I. Cardenas-Navia for their helpful comments on the manuscript; members of the NISC Comparative Sequencing Program for generating the sequence data analyzed here; and S. Anderson and M. Kirby for assistance with FACS analysis. This work supported by the Intramural Research Programs of the National Human Genome Research Institute and National Cancer Institute, National Institutes of Health, USA.

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Authors and Affiliations

  1. Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health (NIH), Bethesda, Maryland, USA

    Todd D Prickett, Neena S Agrawal, Xiaomu Wei, Kristin E Yates, Julia C Cronin & Yardena Samuels

  2. The Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland, USA

    Jimmy C Lin

  3. Surgery Branch, National Cancer Institute, NIH, Bethesda, Maryland, USA

    John R Wunderlich & Steven A Rosenberg

  4. Genome Technology Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA

    Pedro Cruz

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  1. Todd D Prickett
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NISC Comparative Sequencing Program

Contributions

T.D.P. and Y.S. designed the study; J.R.W. and S.A.R. collected and analyzed the melanoma samples; N.S.A., J.C.C., K.E.Y., J.C.L., the NISC Comparative Sequencing Program, P.C. and Y.S. analyzed the genetic data; T.D.P., X.W. and K.E.Y. performed and analyzed the functional data. All authors contributed to the final version of the paper.

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Correspondence to Yardena Samuels.

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Prickett, T., Agrawal, N., Wei, X. et al. Analysis of the tyrosine kinome in melanoma reveals recurrent mutations in ERBB4. Nat Genet 41, 1127–1132 (2009). https://doi.org/10.1038/ng.438

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