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

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*

*Corresponding author for this work

    Research output: Contribution to journalArticle

    155 Citations (Scopus)

    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 BRAF V600 -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 MEK2 C125S, but not the synonymous MEK1 C121S 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.

    Original languageEnglish
    Article number5694
    Pages (from-to)1-9
    Number of pages9
    JournalNature Communications
    Volume5
    DOIs
    Publication statusPublished - 2014

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