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

doi:10.1038/ncomms6694

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

Nat Commun. 2014 Dec 2:5:5694. doi: 10.1038/ncomms6694.

Authors

Georgina V Long¹, Carina Fung², Alexander M Menzies³, Gulietta M Pupo⁴, Matteo S Carlino⁵, Jessica Hyman⁶, Hamideh Shahheydari², Varsha Tembe⁴, John F Thompson⁷, Robyn P Saw⁷, Julie Howle⁸, Nicholas K Hayward⁹, Peter Johansson⁹, Richard A Scolyer¹⁰, Richard F Kefford¹¹, Helen Rizos²

Affiliations

¹ 1] Melanoma Institute Australia, Sydney, New South Wales 2060, Australia [2] Discipline of Medicine, Sydney Medical School, The University of Sydney, Sydney, New South Wales 2006, Australia [3] Mater Hospital, North Sydney, New South Wales 2060, Australia.
² 1] Precision Cancer Therapy Laboratory, Australian School of Advanced Medicine, Macquarie University, Sydney, New South Wales 2109, Australia [2] Westmead Institute for Cancer Research, The University of Sydney at Westmead Millennium Institute, Westmead Hospital, Westmead, New South Wales 2145, Australia.
³ 1] Melanoma Institute Australia, Sydney, New South Wales 2060, Australia [2] Discipline of Medicine, Sydney Medical School, The University of Sydney, Sydney, New South Wales 2006, Australia [3] Department of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, New South Wales 2145, Australia.
⁴ Westmead Institute for Cancer Research, The University of Sydney at Westmead Millennium Institute, Westmead Hospital, Westmead, New South Wales 2145, Australia.
⁵ 1] Melanoma Institute Australia, Sydney, New South Wales 2060, Australia [2] Westmead Institute for Cancer Research, The University of Sydney at Westmead Millennium Institute, Westmead Hospital, Westmead, New South Wales 2145, Australia [3] Department of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, New South Wales 2145, Australia.
⁶ 1] Melanoma Institute Australia, Sydney, New South Wales 2060, Australia [2] Departments of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales 2006, Australia.
⁷ 1] Melanoma Institute Australia, Sydney, New South Wales 2060, Australia [2] Discipline of Surgery, Sydney Medical School, The University of Sydney, Sydney, New South Wales 2006, Australia [3] Departments of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales 2006, Australia.
⁸ 1] Melanoma Institute Australia, Sydney, New South Wales 2060, Australia [2] Discipline of Surgery, Sydney Medical School, The University of Sydney, Sydney, New South Wales 2006, Australia [3] Department of Surgical Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, New South Wales 2145, Australia.
⁹ Oncogenomics Laboratory, QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland 4006, Australia.
¹⁰ 1] Melanoma Institute Australia, Sydney, New South Wales 2060, Australia [2] Departments of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales 2006, Australia [3] Discipline of Pathology, Sydney Medical School, The University of Sydney, Sydney, New South Wales 2006, Australia.
¹¹ 1] Melanoma Institute Australia, Sydney, New South Wales 2060, Australia [2] Discipline of Medicine, Sydney Medical School, The University of Sydney, Sydney, New South Wales 2006, Australia [3] Precision Cancer Therapy Laboratory, Australian School of Advanced Medicine, Macquarie University, Sydney, New South Wales 2109, Australia [4] Westmead Institute for Cancer Research, The University of Sydney at Westmead Millennium Institute, Westmead Hospital, Westmead, New South Wales 2145, Australia.

PMID: 25452114
DOI: 10.1038/ncomms6694

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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*
Melanoma / genetics
Melanoma / 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*
Skin Neoplasms / genetics
Skin Neoplasms / pathology
rac1 GTP-Binding Protein / genetics

Substances

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

Associated data

GEO/GSE61992