J Charles1, C Martel2, F de Fraipont3, M-T Leccia1, C Robert4, B Busser5. 1. Centre de recherche Inserm/UJF U823, institut Albert-Bonniot, BP 170, 38042 Grenoble cedex 9, France; Dermatologie, CHU de Grenoble, CS 10217, 38043 Grenoble cedex 9, France. 2. Centre de recherche Inserm/UJF U823, institut Albert-Bonniot, BP 170, 38042 Grenoble cedex 9, France. 3. Unité médicale de biochimie des cancers et biothérapies, institut de biologie et pathologie, CHU de Grenoble, CS 10217, 38043 Grenoble cedex 09, France. 4. Inserm U981, Institut Gustave-Roussy, 114, rue Edouard-Vaillant, 94805 Villejuif-Paris-Sud, France. 5. Centre de recherche Inserm/UJF U823, institut Albert-Bonniot, BP 170, 38042 Grenoble cedex 9, France. Electronic address: bbusser@chu-grenoble.fr.
Abstract
CONTEXT: In patients with melanoma positive for the BRAF V600 mutation, clinical response to specific BRAF inhibitors is usually rapid and striking, with significant benefits in terms of progression-free survival and overall survival. However, resistance to treatment almost invariably arises, typically within a median timeframe of 6 months. Indeed, very few patients exhibit long-lasting response to these targeted therapies. AIMS: It is essential to better understand the mechanisms of resistance to targeted anti-BRAF therapies in order to increase both response rates and the duration of clinical response to treatment. This literature review describes the signaling pathways involving BRAF and presents recent data from clinical trials with these molecules. Furthermore, we aim to describe the main resistance mechanisms linked with targeted anti-BRAF therapies. METHODS: The keywords (resistance, BRAF, melanoma, targeted therapy, vemurafenib, and dabrafenib) were used to extract relevant articles in the Medline/Pubmed database published before 31 January 2014. DISCUSSION: Improved knowledge and understanding of the mechanisms of resistance to targeted anti-BRAF therapies should enable the development of new therapeutic strategies in order to overcome such resistance and allow more significant and sustained response rates to be achieved among melanoma patients.
CONTEXT: In patients with melanoma positive for the BRAF V600 mutation, clinical response to specific BRAF inhibitors is usually rapid and striking, with significant benefits in terms of progression-free survival and overall survival. However, resistance to treatment almost invariably arises, typically within a median timeframe of 6 months. Indeed, very few patients exhibit long-lasting response to these targeted therapies. AIMS: It is essential to better understand the mechanisms of resistance to targeted anti-BRAF therapies in order to increase both response rates and the duration of clinical response to treatment. This literature review describes the signaling pathways involving BRAF and presents recent data from clinical trials with these molecules. Furthermore, we aim to describe the main resistance mechanisms linked with targeted anti-BRAF therapies. METHODS: The keywords (resistance, BRAF, melanoma, targeted therapy, vemurafenib, and dabrafenib) were used to extract relevant articles in the Medline/Pubmed database published before 31 January 2014. DISCUSSION: Improved knowledge and understanding of the mechanisms of resistance to targeted anti-BRAF therapies should enable the development of new therapeutic strategies in order to overcome such resistance and allow more significant and sustained response rates to be achieved among melanomapatients.
Authors: Chi Yan; Nabil Saleh; Jinming Yang; Caroline A Nebhan; Anna E Vilgelm; E Premkumar Reddy; Joseph T Roland; Douglas B Johnson; Sheau-Chiann Chen; Rebecca L Shattuck-Brandt; Gregory D Ayers; Ann Richmond Journal: Mol Cancer Date: 2021-06-06 Impact factor: 41.444