Progression of RAS-Mutant Leukemia during RAF Inhibitor Treatment

• Published in: The New England journal of medicine Vol. 367; no. 24; pp. 2316 - 2321
• Main Authors: Callahan, Margaret K, Rampal, Raajit, Harding, James J, Klimek, Virginia M, Chung, Young Rock, Merghoub, Taha, Wolchok, Jedd D, Solit, David B, Rosen, Neal, Abdel-Wahab, Omar, Levine, Ross L, Chapman, Paul B
• Format: Journal Article
• Language: English
• Published: Waltham, MA Massachusetts Medical Society 13-12-2012
• Series: Brief Report
• Subjects: Aged; Biological and medical sciences; Cell Proliferation - drug effects; Disease Progression; General aspects; Genes, ras; Hematologic and hematopoietic diseases; Humans; Indoles - adverse effects; Indoles - therapeutic use; Leukemia, Myelomonocytic, Chronic - chemically induced; Leukemia, Myelomonocytic, Chronic - genetics; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Leukocyte Count; Male; Medical sciences; Melanoma - drug therapy; Melanoma - genetics; Mutation; Protein Kinase Inhibitors - adverse effects; Protein Kinase Inhibitors - therapeutic use; Proto-Oncogene Proteins B-raf - antagonists & inhibitors; Proto-Oncogene Proteins B-raf - genetics; Sulfonamides - adverse effects; Sulfonamides - therapeutic use; Vemurafenib; Medicine; Prognosis; Treatment; C-Onc gene; Leukemia; Evolution; Malignant hemopathy; Inhibitor; Ras gene; Protooncogene; Cancer
• ISSN: 0028-4793; 1533-4406
• DOI: 10.1056/NEJMoa1208958

A man with undiagnosed chronic myelomonocytic leukemia began treatment with vemurafenib for BRAF-mutant metastatic melanoma. His white-cell count soared and then dropped when the drug was withdrawn. The leukemia cells contained an RAS mutation that became more active with RAF inhibition.
Approximately 50% of patients with metastatic melanoma harbor a somatic V600E mutation — or, less frequently, a V600K mutation — in the BRAF kinase.
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These activating mutations drive increased ERK signaling, promoting the proliferation and survival of melanoma cells.
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Selective RAF inhibitors, such as vemurafenib and dabrafenib, inhibit ERK signaling and arrest growth in tumors with BRAF V600E or BRAF V600K mutations.
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Treatment with vemurafenib or dabrafenib induces tumor regression in more than half of patients with BRAF V600E–mutant metastatic melanoma. Both drugs also improve the rate of progression-free survival, as compared with dacarbazine.
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Vemurafenib . . .