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L576P KIT mutation in anal melanomas correlates with KIT protein expression and is sensitive to specific kinase inhibition
Author(s) -
Antonescu Cristina R.,
Busam Klaus J.,
Francone Todd D.,
Wong Grace C.,
Guo Tianhua,
Agaram Narasimhan P.,
Besmer Peter,
Jungbluth Achim,
Gimbel Mark,
Chen ChinTung,
Veach Darren,
Clarkson Bayard D.,
Paty Philip B.,
Weiser Martin R.
Publication year - 2007
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.22681
Subject(s) - neuroblastoma ras viral oncogene homolog , dasatinib , cancer research , imatinib , pdgfra , melanoma , mutation , mucosal melanoma , proto oncogene proteins c kit , imatinib mesylate , mutant , biology , medicine , kras , microbiology and biotechnology , gist , gene , stromal cell , genetics , stem cell , myeloid leukemia , haematopoiesis , stem cell factor
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 KIT L576P 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.