Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0278883 (metastatic melanoma)
 6,224 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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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PMID:Analysis of the tyrosine kinome in melanoma reveals recurrent mutations in ERBB4. 2002 3

Melanoma is curable when it is at an early phase but is lethal once it becomes metastatic. The recent development of BRAF(V600E) inhibitors (BIs) showed great promise in treating metastatic melanoma, but resistance developed quickly in the treated patients, and these inhibitors are not effective on melanomas that express wild-type BRAF. Alternative therapeutic strategies for metastatic melanoma are urgently needed. Here we report that ERBB3, a member of the epidermal growth factor receptor family, is required for the formation of lung metastasis from both the BI-sensitive melanoma cell line, MA-2, and the BI-resistant melanoma cell line, 451Lu-R. Further analyses revealed that ERBB3 does not affect the initial seeding of melanoma cells in lung but is required for their further development into overt metastases, indicating that ERBB3 might be essential for the survival of melanoma cells after they reach the lung. Consistent with this, the ERBB3 ligand, NRG1, is highly expressed in mouse lungs and induces ERBB3-depdnent phosphorylation of AKT in both MA-2 and 451Lu-R cells in vitro. These findings suggest that ERBB3 may serve as a target for treating metastatic melanomas that are resistant to BIs. In support of this, administration of the pan-ERBB inhibitor, canertinib, significantly suppresses the metastasis formation of BI-resistant melanoma cell lines.
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PMID:ERBB3 is required for metastasis formation of melanoma cells. 2500 Feb 58