NRAS mutant melanoma - undrugable?

University of California San Francisco, Department for Dermatology, Mt. Zion Cancer Research Center, California, USA.
Oncotarget (Impact Factor: 6.63). 04/2013; 4(4):494-5.
Source: PubMed

ABSTRACT Mutations in the three rat sarcoma (RAS) family members NRAS (neuroblastoma-RAS), HRAS (Harvey-RAS) and KRAS (Kirsten-RAS) are found in one third of human cancers. Among the first oncogenes discovered in cutaneous melanoma was NRAS, which is mutant in up to 20% of tumors causing aberrant signaling in several downstream cascades. Despite, being a highly relevant therapeutic target, design of small molecules selectively inhibiting mutant NRAS in melanoma, to date, remains an unsolved challenge. The end?

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    ABSTRACT: The aim of this study was to evaluate a series of primary melanomas of the female urogenital tract for oncogenic mutations in KIT, NRAS and BRAF in order to identify patients who may be amenable to targeted therapy. We reviewed twenty-four cases of female urogenital tract melanomas and used Sanger sequencing analysis for the detection of oncogenic mutations in exons 9, 11, 13, and 17 of KIT; exons 2 and 3 of NRAS; and exon 15 of BRAF. Twenty-four patients were included: fourteen vaginal melanomas, four cervical melanomas, five urethral melanomas and one vulvar melanoma. NRAS mutations (4/24, 21%) were more prevalent than KIT mutations (1/24, 4%), while BRAF mutations were absent. Three of four NRAS mutations were present in vaginal melanomas (21%), mainly affecting codon 61 (3/4). They were mutually exclusive with the KIT mutation. The KIT mutation was present in a vaginal melanoma and affected exon 17. Melanomas of the female urogenital tract relatively commonly harbor mutations in NRAS; this makes NRAS an interesting therapeutic target for these patients in the advanced setting. KIT mutations were rare in our study in contrast to some previous reports. We cannot exclude that anatomical site-related differences and/or population related differences in KIT mutation frequency exist within urogenital tract melanomas.
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