L576P KIT mutation in anal melanomas correlates with KIT protein expression and is sensitive to specific kinase inhibition Journal Article
| Authors: | Antonescu, C. R.; Busam, K. J.; Francone, T. D.; Wong, G. C.; Guo, T.; Agaram, N. P.; Besmer, P.; Jungbluth, A.; Gimbel, M.; Chen, C. T.; Veach, D.; Clarkson, B. D; Paty, P. B.; Weiser, M. R. |
| Article Title: | L576P KIT mutation in anal melanomas correlates with KIT protein expression and is sensitive to specific kinase inhibition |
| Abstract: | Activating mutations in either BRAF or NRAS are seen in a significant number of malignant melanomas, but their incidence appears to be dependent to ultraviolet light exposure. Thus, BRAF mutations have the highest incidence in non-chronic sun damaged (CSD), and are uncommon in acral, mucosal and CSD melanomas. More recently, activating KIT mutations have been described in rare cases of metastatic melanoma, without further reference to their clinical phenotypes. This finding is intriguing since KIT expression is downregulated in most melanomas progressing to more aggressive lesions. In this study, we investigated a group of anal melanomas for the presence of BRAF, NRAS. KIT and PDGFRA mutations. A heterozygous KIT exon 11 L576P substitution was identified in 3 of 20 cases tested. The 3 KIT mutation-carrying tumors were strongly immunopositive for KIT protein. No KIT mutations were identified in tumors with less than 4+ KIT immunostaining. NRAS mutation was identified in one tumor. No BRAF or PDGFRA mutations were identified in either KIT positive or negative anal melanomas. In vitro drug testing of stable transformant Ba/F3 KIT L576P mutant cells showed sensitivity for dasatinib (previously known as BMS-354825), a dual SRC/ABL kinase inhibitor, and imatinib. However, compared to an imatinib-sensitive KIT mutant, dasatinib was potent at lower doses than imatinib in the KITL576P mutant. These results suggest that a subset of anal melanomas show activating KIT mutations, which are susceptible for therapy with specific kinase inhibitors. © 2007 Wiley-Liss, Inc. |
| Keywords: | immunohistochemistry; adult; clinical article; controlled study; human tissue; protein phosphorylation; aged; aged, 80 and over; middle aged; gene mutation; human cell; mutation; drug targeting; cell proliferation; animals; in situ hybridization, fluorescence; imatinib; proto-oncogene proteins c-kit; melanoma; apoptosis; enzyme inhibition; gene expression; cell line; genotype; drug effect; dose-response relationship, drug; transfection; dasatinib; pyrimidines; phosphorylation; protein tyrosine kinase inhibitor; protein kinase inhibitors; oncogene; blotting, western; reverse transcriptase polymerase chain reaction; tyrosine kinase receptor; immunoprecipitation; base sequence; kit; dna mutational analysis; nilotinib; thiazoles; b raf kinase; concentration response; complementary dna; braf mutations; anus neoplasms; anus tumor; nras; anal; mucosal |
| Journal Title: | International Journal of Cancer |
| Volume: | 121 |
| Issue: | 2 |
| ISSN: | 0020-7136 |
| Publisher: | John Wiley & Sons |
| Date Published: | 2007-07-15 |
| Start Page: | 257 |
| End Page: | 264 |
| Language: | English |
| DOI: | 10.1002/ijc.22681 |
| PUBMED: | 17372901 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 76" - "Export Date: 17 November 2011" - "CODEN: IJCNA" - "Source: Scopus" |
