title: 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.affiliation: 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.
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Long
authors.affiliation: 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.
authors.forename: Carina
authors.initials: C
authors.lastname: Fung
authors.affiliation: 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.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Menzies
authors.affiliation: Westmead Institute for Cancer Research, The University of Sydney at Westmead Millennium Institute, Westmead Hospital, Westmead, New South Wales 2145, Australia.
authors.forename: Gulietta M
authors.initials: GM
authors.lastname: Pupo
authors.affiliation: 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.
authors.forename: Matteo S
authors.initials: MS
authors.lastname: Carlino
authors.affiliation: 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.
authors.forename: Jessica
authors.initials: J
authors.lastname: Hyman
authors.affiliation: 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.
authors.forename: Hamideh
authors.initials: H
authors.lastname: Shahheydari
authors.affiliation: Westmead Institute for Cancer Research, The University of Sydney at Westmead Millennium Institute, Westmead Hospital, Westmead, New South Wales 2145, Australia.
authors.forename: Varsha
authors.initials: V
authors.lastname: Tembe
authors.affiliation: 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.
authors.forename: John F
authors.initials: JF
authors.lastname: Thompson
authors.affiliation: 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.
authors.forename: Robyn P
authors.initials: RP
authors.lastname: Saw
authors.affiliation: 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.
authors.forename: Julie
authors.initials: J
authors.lastname: Howle
authors.affiliation: Oncogenomics Laboratory, QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland 4006, Australia.
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: Hayward
authors.affiliation: Oncogenomics Laboratory, QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland 4006, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Johansson
authors.affiliation: 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.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Scolyer
authors.affiliation: 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.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Kefford
authors.affiliation: 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.
authors.forename: Helen
authors.initials: H
authors.lastname: Rizos
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D048369:MAP Kinase Kinase 1 / Q000235:genetics*; D048370:MAP Kinase Kinase 2 / Q000235:genetics*; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary; D008565:Membrane Proteins / Q000235:genetics*; D010091:Oximes / Q000008:administration & dosage; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D011728:Pyridones / Q000008:administration & dosage; D011744:Pyrimidinones / Q000008:administration & dosage; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D020830:rac1 GTP-Binding Protein / Q000235:genetics
chemical_list: D007093:Imidazoles; D008565:Membrane Proteins; D010091:Oximes; D011728:Pyridones; D011744:Pyrimidinones; C107953:RAC1 protein, human; C560077:trametinib; C482128:MAP2K2 protein, human; D019869:Phosphatidylinositol 3-Kinases; C491754:AKT3 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D020830:rac1 GTP-Binding Protein; C561627:dabrafenib