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

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.

• 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
• Journal: Nature communications (Nat Commun) Vol. 5 Pg. 5694 (Dec 02 2014) ISSN: 2041-1723 [Electronic] England
• PMID: 25452114 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Imidazoles
• Membrane Proteins
• Oximes
• Pyridones
• Pyrimidinones
• RAC1 protein, human
• trametinib
• MAP2K2 protein, human
• Phosphatidylinositol 3-Kinases
• AKT3 protein, human
• BRAF protein, human
• Proto-Oncogene Proteins B-raf
• Proto-Oncogene Proteins c-akt
• MAP Kinase Kinase 1
• MAP Kinase Kinase 2
• MAP2K1 protein, human
• GTP Phosphohydrolases
• NRAS protein, human
• rac1 GTP-Binding Protein
• dabrafenib

Topics

• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Drug Resistance, Neoplasm (genetics)
• GTP Phosphohydrolases (genetics)
• Humans
• Imidazoles (administration & dosage)
• MAP Kinase Kinase 1 (genetics)
• MAP Kinase Kinase 2 (genetics)
• Melanoma (drug therapy, genetics, secondary)
• Membrane Proteins (genetics)
• Oximes (administration & dosage)
• Phosphatidylinositol 3-Kinases (metabolism)
• Proto-Oncogene Proteins B-raf (genetics)
• Proto-Oncogene Proteins c-akt (genetics)
• Pyridones (administration & dosage)
• Pyrimidinones (administration & dosage)
• Skin Neoplasms (drug therapy, genetics, pathology)
• rac1 GTP-Binding Protein (genetics)