title: MAP kinase pathway alterations in BRAF-mutant melanoma patients with acquired resistance to combined RAF/MEK inhibition.
abstract: Treatment of BRAF-mutant melanoma with combined dabrafenib and trametinib, which target RAF and the downstream MAP-ERK kinase (MEK)1 and MEK2 kinases, respectively, improves progression-free survival and response rates compared with dabrafenib monotherapy. Mechanisms of clinical resistance to combined RAF/MEK inhibition are unknown. We performed whole-exome sequencing (WES) and whole-transcriptome sequencing (RNA-seq) on pretreatment and drug-resistant tumors from five patients with acquired resistance to dabrafenib/trametinib. In three of these patients, we identified additional mitogen-activated protein kinase (MAPK) pathway alterations in the resistant tumor that were not detected in the pretreatment tumor, including a novel activating mutation in MEK2 (MEK2(Q60P)). MEK2(Q60P) conferred resistance to combined RAF/MEK inhibition in vitro, but remained sensitive to inhibition of the downstream kinase extracellular signal-regulated kinase (ERK). The continued MAPK signaling-based resistance identified in these patients suggests that alternative dosing of current agents, more potent RAF/MEK inhibitors, and/or inhibition of the downstream kinase ERK may be needed for durable control of BRAF-mutant melanoma.
authors.affiliation: 1Department of Medical Oncology, Dana-Farber Cancer Institute; 2Department of Medicine, Brigham and Women's Hospital; 3Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston; 4Broad Institute of Harvard and MIT; and 5Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts.
authors.forename: Nikhil
authors.initials: N
authors.lastname: Wagle
authors.forename: Eliezer M
authors.initials: EM
authors.lastname: Van Allen
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Treacy
authors.forename: Dennie T
authors.initials: DT
authors.lastname: Frederick
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Cooper
authors.forename: Amaro
authors.initials: A
authors.lastname: Taylor-Weiner
authors.forename: Mara
authors.initials: M
authors.lastname: Rosenberg
authors.forename: Eva M
authors.initials: EM
authors.lastname: Goetz
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Sullivan
authors.forename: Deborah N
authors.initials: DN
authors.lastname: Farlow
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Friedrich
authors.forename: Kristin
authors.initials: K
authors.lastname: Anderka
authors.forename: Danielle
authors.initials: D
authors.lastname: Perrin
authors.forename: Cory M
authors.initials: CM
authors.lastname: Johannessen
authors.forename: Aaron
authors.initials: A
authors.lastname: McKenna
authors.forename: Kristian
authors.initials: K
authors.lastname: Cibulskis
authors.forename: Gregory
authors.initials: G
authors.lastname: Kryukov
authors.forename: Eran
authors.initials: E
authors.lastname: Hodis
authors.forename: Donald P
authors.initials: DP
authors.lastname: Lawrence
authors.forename: Sheila
authors.initials: S
authors.lastname: Fisher
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.forename: Stacey B
authors.initials: SB
authors.lastname: Gabriel
authors.forename: Scott L
authors.initials: SL
authors.lastname: Carter
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Wargo
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D010091:Oximes / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics*; D011728:Pyridones / Q000627:therapeutic use; D011744:Pyrimidinones / Q000627:therapeutic use; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D048490:raf Kinases / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048490:raf Kinases; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; C561627:dabrafenib