L576P KIT mutation in anal melanomas correlates with KIT protein expression and is sensitive to specific kinase inhibition.
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.
Antonescu
Cristina R
CR
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. antonesc@mskcc.org
Busam
Klaus J
KJ
Francone
Todd D
TD
Wong
Grace C
GC
Guo
Tianhua
T
Agaram
Narasimhan P
NP
Besmer
Peter
P
Jungbluth
Achim
A
Gimbel
Mark
M
Chen
Chin-Tung
CT
Veach
Darren
D
Clarkson
Bayard D
BD
Paty
Philip B
PB
Weiser
Martin R
MR
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001005:Anus Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D001483:Base Sequence; D015153:Blotting, Western; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004252:DNA Mutational Analysis; D000069439:Dasatinib; D004305:Dose-Response Relationship, Drug; D005260:Female; D015870:Gene Expression; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008875:Middle Aged; D009154:Mutation; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013844:Thiazoles / Q000494:pharmacology; D014162:Transfection
D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D019009:Proto-Oncogene Proteins c-kit; D000069439:Dasatinib