Article

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?

0 Bookmarks
 · 
60 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: Melanoma is an aggressive disease characterized by a complex etiology. The discovery of key driving mutations (primarily BRAF mutations) led to the development of specific molecular inhibitors providing clinical benefit. Areas covered: Although BRAF-specific drugs have perhaps yielded the best results in melanoma-targeted therapy, there still remain several limitations, mostly due to the emergence of resistance and the lack of efficacy in patients without BRAF mutation. Novel drugs are currently being tested in clinical trials and showed encouraging results. Such drugs can specifically target molecular pathways aberrantly activated or repressed during melanoma development (targeted therapy) or act in a way to enhance the host immune system to fight cancer (immunotherapy). Here we provide a detailed overview of the current clinical strategies, which lay beyond BRAF-targeted therapy, spanning from molecular-targeted therapy to immunotherapy and to combination therapy. Expert opinion: Major advances in our understanding of the mechanisms behind melanoma development have led to the implementation of novel therapeutic drugs. Unfortunately, tools allowing prediction of responsiveness to a given treatment are not available yet. The increasing availability of high-throughput technologies will allow the elucidation of molecular mechanisms underlying responsiveness to cancer therapy and unveil an increased number of potential therapeutic targets.
    Expert opinion on biological therapy 03/2014; · 3.22 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Melanoma is the least common form of skin cancer, but it is responsible for the majority of skin cancer deaths. Traditional therapeutics and immunomodulatory agents have not shown much efficacy against metastatic melanoma. Agents that target the RAS/RAF/MEK/ERK (MAPK) signaling pathway-the BRAF inhibitors vemurafenib and dabrafenib, and the MEK1/2 inhibitor trametinib-have increased survival in patients with metastatic melanoma. Further, the combination of dabrafenib and trametinib has been shown to be superior to single agent therapy for the treatment of metastatic melanoma. However, resistance to these agents develops rapidly. Studies of additional agents and combinations targeting the MAPK, PI3K/AKT/mTOR (PI3K), c-kit, and other signaling pathways are currently underway. Furthermore, studies of phytochemicals have yielded promising results against proliferation, survival, invasion, and metastasis by targeting signaling pathways with established roles in melanomagenesis. The relatively low toxicities of phytochemicals make their adjuvant use an attractive treatment option. The need for improved efficacy of current melanoma treatments calls for further investigation of each of these strategies. In this review, we will discuss synthetic small molecule inhibitors, combined therapies and current progress in the development of phytochemical therapies. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Cancer letters. 01/2015;
  • Source
    [Show abstract] [Hide abstract]
    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.
    Gynecologic Oncology 05/2014; · 3.69 Impact Factor

Full-text (2 Sources)

Download
22 Downloads
Available from
May 20, 2014