• Omar Abdel-Wahab, Virginia M Klimek, Alisa A Gaskell, Agnes Viale, Donavan Cheng, Eunhee Kim, Raajit Rampal, Mark Bluth, James J Harding, Margaret K Callahan, Taha Merghoub, Michael F Berger, David B Solit, Neal Rosen, Ross L Levine, and Paul B Chapman.
• 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.
• Cancer Discov. 2014 May 1; 4 (5): 538-45.

AbstractVemurafenib, 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.

49 keywords...

hide…