title: Progression of RAS-mutant leukemia during RAF inhibitor treatment.
abstract: Vemurafenib, a selective RAF inhibitor, extends survival among patients with BRAF V600E-mutant melanoma. Vemurafenib inhibits ERK signaling in BRAF V600E-mutant cells but activates ERK signaling in BRAF wild-type cells. This paradoxical activation of ERK signaling is the mechanistic basis for the development of RAS-mutant squamous-cell skin cancers in patients treated with RAF inhibitors. We report the accelerated growth of a previously unsuspected RAS-mutant leukemia in a patient with melanoma who was receiving vemurafenib. Exposure to vemurafenib induced hyperactivation of ERK signaling and proliferation of the leukemic cell population, an effect that was reversed on drug withdrawal.
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Margaret K
authors.initials: MK
authors.lastname: Callahan
authors.forename: Raajit
authors.initials: R
authors.lastname: Rampal
authors.forename: James J
authors.initials: JJ
authors.lastname: Harding
authors.forename: Virginia M
authors.initials: VM
authors.lastname: Klimek
authors.forename: Young Rock
authors.initials: YR
authors.lastname: Chung
authors.forename: Taha
authors.initials: T
authors.lastname: Merghoub
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
authors.forename: David B
authors.initials: DB
authors.lastname: Solit
authors.forename: Neal
authors.initials: N
authors.lastname: Rosen
authors.forename: Omar
authors.initials: O
authors.lastname: Abdel-Wahab
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.forename: Paul B
authors.initials: PB
authors.lastname: Chapman
mesh_terms: D000368:Aged; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D011905:Genes, ras; D006801:Humans; D007211:Indoles / Q000009:adverse effects* / Q000627:therapeutic use; D015477:Leukemia, Myelomonocytic, Chronic / Q000139:chemically induced / Q000235:genetics*; D007958:Leukocyte Count; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics*; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D013449:Sulfonamides / Q000009:adverse effects* / Q000627:therapeutic use; D000077484:Vemurafenib
chemical_list: D007211:Indoles; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D000077484:Vemurafenib; D048493:Proto-Oncogene Proteins B-raf