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GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA

Rivista di Dermatologia e Malattie Sessualmente Trasmesse


Official Journal of the Italian Society of Dermatology and Sexually Transmitted Diseases
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Giornale Italiano di Dermatologia e Venereologia 2018 Mar 29

DOI: 10.23736/S0392-0488.18.05970-9

Copyright © 2018 EDIZIONI MINERVA MEDICA

lingua: Inglese

The window of opportunities for targeted therapy in BRAFwt/NRASwt/KITwt melanoma. Biology and clinical implications of fusion proteins and other mutations

Marina BERGER 1, Georg RICHTIG 1, 2 , Karl KASHOFER 3, Ariane AIGELSREITER 3, Erika RICHTIG 1

1 Department of Dermatology, Medical University of Graz, Graz, Austria; 2 Otto Loewi Research Center, Pharmacology Section, Medical University of Graz, Graz, Austria; 3 Institute for Pathology, Medical University of Graz, Graz, Austria


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Treatment options in advanced melanoma have been subject to a major change over the last years. The discovery of the oncogenic point mutation BRAFV600E and subsequently developed BRAF inhibitors had a major impact on patient’s survival. Further important mutations have been found in the NRAS gene, although not yet druggable, and others involve c-kit in acral and mucosal melanoma. Imatinib was shown to achieve high response rates in c-kit mutated melanoma. Despite good response rates in these targeted therapies and introduction of immunotherapy, there are still patients left, who develop resistance upon therapy or patients without the option of targeted therapy. Therefore it is necessary to identify further therapeutic options for this subset of patients. Several new mutations have been described so far that might be suitable for targeted therapy or useful as clinical biomarkers. Alterations in various receptor tyrosine kinases lead to constitutively activated downstream signalling and might be responsible for non-response to common therapies. In contrast, tyrosine kinase inhibitors such as sunitinib or nilotinib could be suitable for patients harbouring those alterations. Additionally, chromosomal rearrangements have been described in many different cancer types, resulting in oncogenic fusion proteins that involve BRAF, ROS1, NTRK, ALK and others. These are an emerging therapeutic field, especially in spitzoid melanomas. Further mutations have been detected in the neurofibromin 1 and RAC1 gene, although the clinical relevance is still not fully revealed. Within this review we will summarize the current evidence and focus on possible further upcoming targets and therapeutic opportunities in BRAFwt/NRASwt/KITwt melanoma.


KEY WORDS: Fusion proteins - NF1 - RAC1 - Targeted therapy - Receptor tyrosine kinase

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Publication History

Article first published online: March 29, 2018
Manuscript accepted: March 15, 2018
Manuscript received: February 23, 2018

Per citare questo articolo

Berger M, Richtig G, Kashofer K, Aigelsreiter A, Richtig E. The window of opportunities for targeted therapy in BRAFwt/NRASwt/KITwt melanoma. Biology and clinical implications of fusion proteins and other mutations. G Ital Dermatol Venereol 2018 Mar 29. DOI: 10.23736/S0392-0488.18.05970-9

Corresponding author e-mail

georg.richtig@medunigraz.at