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 and Helen Rizos ()
Additional contact information
Georgina V. Long: Melanoma Institute Australia
Carina Fung: Precision Cancer Therapy Laboratory, Australian School of Advanced Medicine, Macquarie University
Alexander M. Menzies: Melanoma Institute Australia
Gulietta M. Pupo: Westmead Institute for Cancer Research, The University of Sydney at Westmead Millennium Institute, Westmead Hospital
Matteo S. Carlino: Melanoma Institute Australia
Jessica Hyman: Melanoma Institute Australia
Hamideh Shahheydari: Precision Cancer Therapy Laboratory, Australian School of Advanced Medicine, Macquarie University
Varsha Tembe: Westmead Institute for Cancer Research, The University of Sydney at Westmead Millennium Institute, Westmead Hospital
John F. Thompson: Melanoma Institute Australia
Robyn P. Saw: Melanoma Institute Australia
Julie Howle: Melanoma Institute Australia
Nicholas K. Hayward: Oncogenomics Laboratory, QIMR Berghofer Medical Research Institute, Herston
Peter Johansson: Oncogenomics Laboratory, QIMR Berghofer Medical Research Institute, Herston
Richard A. Scolyer: Melanoma Institute Australia
Richard F. Kefford: Melanoma Institute Australia
Helen Rizos: Precision Cancer Therapy Laboratory, Australian School of Advanced Medicine, Macquarie University

Nature Communications, 2014, vol. 5, issue 1, 1-9

Abstract: 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.

Date: 2014
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/ncomms6694 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6694

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/ncomms6694

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().