title: Efficacy of intermittent combined RAF and MEK inhibition in a patient with concurrent BRAF- and NRAS-mutant malignancies.
abstract: Vemurafenib, a RAF inhibitor, extends survival in patients with BRAF(V600)-mutant melanoma but activates extracellular signal-regulated kinase (ERK) signaling in RAS-mutant cells. In a patient with a BRAF(V600K)-mutant melanoma responding to vemurafenib, we observed accelerated progression of a previously unrecognized NRAS-mutant leukemia. We hypothesized that combining vemurafenib with a MAP-ERK kinase (MEK) inhibitor would inhibit ERK activation in the melanoma and prevent ERK activation by vemurafenib in the leukemia, and thus suppress both malignancies. We demonstrate that intermittent administration of vemurafenib led to a near-complete remission of the melanoma, and the addition of the MEK inhibitor cobimetinib (GDC-0973) caused suppression of vemurafenib-induced leukemic proliferation and ERK activation. Antimelanoma and antileukemia responses have been maintained for nearly 20 months, as documented by serial measurements of tumor-derived DNA in plasma in addition to conventional radiographic and clinical assessments of response. These data support testing of intermittent ERK pathway inhibition in the therapy for both RAS-mutant leukemia and BRAF-mutant melanoma.
authors.affiliation: 1Human Oncology and Pathogenesis Program, 2Leukemia Service, 3Gastrointestinal Oncology Service, 4Melanoma and Immunotherapeutics Service, Department of Medicine, 5Molecular Diagnostics Service, Department of Pathology, 6Department of Radiology, 7Center for Molecular Oncology, 8Ludwig Center for Cancer Immunotherapy, and 9Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center; and 10Weill Cornell Medical College, New York, New York.
authors.forename: Omar
authors.initials: O
authors.lastname: Abdel-Wahab
authors.forename: Virginia M
authors.initials: VM
authors.lastname: Klimek
authors.forename: Alisa A
authors.initials: AA
authors.lastname: Gaskell
authors.forename: Agnes
authors.initials: A
authors.lastname: Viale
authors.forename: Donavan
authors.initials: D
authors.lastname: Cheng
authors.forename: Eunhee
authors.initials: E
authors.lastname: Kim
authors.forename: Raajit
authors.initials: R
authors.lastname: Rampal
authors.forename: Mark
authors.initials: M
authors.lastname: Bluth
authors.forename: James J
authors.initials: JJ
authors.lastname: Harding
authors.forename: Margaret K
authors.initials: MK
authors.lastname: Callahan
authors.forename: Taha
authors.initials: T
authors.lastname: Merghoub
authors.forename: Michael F
authors.initials: MF
authors.lastname: Berger
authors.forename: David B
authors.initials: DB
authors.lastname: Solit
authors.forename: Neal
authors.initials: N
authors.lastname: Rosen
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.forename: Paul B
authors.initials: PB
authors.lastname: Chapman
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001384:Azetidines / Q000008:administration & dosage* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004273:DNA, Neoplasm / Q000032:analysis; D004334:Drug Administration Schedule; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors / Q000235:genetics; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000627:therapeutic use; D007938:Leukemia / Q000139:chemically induced / Q000517:prevention & control*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D009154:Mutation; D009360:Neoplastic Cells, Circulating / Q000187:drug effects; D010880:Piperidines / Q000008:administration & dosage* / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics; D013449:Sulfonamides / Q000008:administration & dosage* / Q000627:therapeutic use; D000077484:Vemurafenib
chemical_list: D000970:Antineoplastic Agents; D001384:Azetidines; D004273:DNA, Neoplasm; D007211:Indoles; D008565:Membrane Proteins; D010880:Piperidines; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; C574276:cobimetinib