Increased MAPK reactivation in early resistance to dabrafenib/trametinib combination therapy of BRAF-mutant metastatic melanoma View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2014-12-02

AUTHORS

Georgina V. Long, Carina Fung, Alexander M. Menzies, Gulietta M. Pupo, Matteo S. Carlino, Jessica Hyman, Hamideh Shahheydari, Varsha Tembe, John F. Thompson, Robyn P. Saw, Julie Howle, Nicholas K. Hayward, Peter Johansson, Richard A. Scolyer, Richard F. Kefford, Helen Rizos

ABSTRACT

One-third of BRAF-mutant metastatic melanoma patients treated with combined BRAF and MEK inhibition progress within 6 months. Treatment options for these patients remain limited. Here we analyse 20 BRAFV600-mutant melanoma metastases derived from 10 patients treated with the combination of dabrafenib and trametinib for resistance mechanisms and genetic correlates of response. Resistance mechanisms are identified in 9/11 progressing tumours and MAPK reactivation occurred in 9/10 tumours, commonly via BRAF amplification and mutations activating NRAS and MEK2. Our data confirming that MEK2C125S, but not the synonymous MEK1C121S protein, confers resistance to combination therapy highlight the functional differences between these kinases and the preponderance of MEK2 mutations in combination therapy-resistant melanomas. Exome sequencing did not identify additional progression-specific resistance candidates. Nevertheless, most melanomas carried additional oncogenic mutations at baseline (for example, RAC1 and AKT3) that activate the MAPK and PI3K pathways and are thus predicted to diminish response to MAPK inhibitors. More... »

PAGES

5694

References to SciGraph publications

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  • Journal

    TITLE

    Nature Communications

    ISSUE

    1

    VOLUME

    5

    Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/ncomms6694

    DOI

    http://dx.doi.org/10.1038/ncomms6694

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1020390905

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/25452114


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