Analysis of the tyrosine kinome in melanoma reveals recurrent mutations in ERBB4
Open accessAbstract
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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Mutations in ERBB4 were identified in cancer, particularly melanoma, lung adenocarcinoma, and medulloblastoma.
“Similarly, mutations in ERBB4 were identified in cancer, particularly melanoma (Prickett et al., 2009), lung adenocarcinoma (Ding et al., 2008), and medulloblastoma (Gilbertson et al., 2001).”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Prickett et al., 2009
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- Authors
- Program, N. C. S., Prickett, T. D., Agrawal, N. S., Wei, X., Yates, K. E., Lin, J. C., Wunderlich, J. R., Cronin, J. C., Cruz, P., Rosenberg, S. A., & Samuels, Y.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Samuels, Yardena
- Venue
- Nature Genetics
- Published
- 2009-08-30
- Volume
- 41
- Issue
- 10
- Pages
- 1127-1132
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC2897709
- OpenAlex
- W2018169163
- Cited by
- 352
- References
- 32
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 4 · 2023: 14 · 2022: 12 · 2021: 13 · 2020: 13 · 2019: 14 · 2018: 14 · 2017: 18 · 2016: 17 · 2015: 26 · 2014: 39 · 2013: 37 · 2012: 38
- FWCI
- 15.95
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Human Genome Research Institute (Z01HG200337, ZIAHG200337)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
- Keywords
- melanoma, ErbB4, somatic mutations, tyrosine kinase, metastatic cutaneous melanoma, kinase domain mutations, missense mutations, kinase activity, cell transformation, lapatinib, Flt-1, Pyk2, therapeutic target, personalized treatment
- MeSH terms
- Lapatinib, Animals, Antineoplastic Agents, Cell Line, Cell Transformation, Neoplastic, Humans, Melanoma, Mutation, Protein-Tyrosine Kinases, Quinazolines, Skin Neoplasms, RNA Interference, Cell Proliferation, Mice, ErbB Receptors, Receptor, ErbB-4
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