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PMID: 23134356 Published · ppublish English Case Reports Journal Article

Progression of RAS-mutant leukemia during RAF inhibitor treatment.

The New England journal of medicine ·Vol. 367 ·No. 24 ·2012-12-13 ·Pages 2316-21

Callahan MK, Rampal R, Harding JJ, Klimek VM, Chung YR, Merghoub T, Wolchok JD, Solit DB, Rosen N, Abdel-Wahab O, Levine RL, Chapman PB

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.

MeSH Terms
Aged Cell Proliferation/drug effects Disease Progression Genes, ras Humans Indoles/adverse effects,therapeutic use Leukemia, Myelomonocytic, Chronic/chemically induced,genetics Leukocyte Count Male Melanoma/drug therapy,genetics Mutation Protein Kinase Inhibitors/adverse effects,therapeutic use Proto-Oncogene Proteins B-raf/antagonists & inhibitors,genetics Sulfonamides/adverse effects,therapeutic use Vemurafenib
Chemicals
Indoles Protein Kinase Inhibitors Sulfonamides Vemurafenib Proto-Oncogene Proteins B-raf
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Callahan Margaret K
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
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
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Article Info
Journal
The New England journal of medicine
Abbr.
N Engl J Med
ISSN
1533-4406
DOI
10.1056/NEJMoa1208958
Published
2012-12-13
Epub
2012-00-07
Pages
2316-21
Language
English
Region
United States
NLM ID
0255562
PMCID
PMC3627494
Subset
IM
Grants
NCI NIH HHS · R25 CA020449 · United States
NCI NIH HHS · T32 CA009207 · United States
External Links
PubMed source DOI: 10.1056/NEJMoa1208958 PMC Full Text View journal details
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