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- Title
BRAF inhibitor-associated ERK activation drives development of chronic lymphocytic leukemia.
- Authors
Yaktapour, Niuscha; Meiss, Frank; Mastroianni, Justin; Zenz, Thorsten; Andrlova, Hana; Mathew, Nimitha R; Claus, Rainer; Hutter, Barbara; Fröhling, Stefan; Brors, Benedikt; Pfeifer, Dietmar; Pantic, Milena; Bartsch, Ingrid; Spehl, Timo S; Meyer, Philipp T; Duyster, Justus; Zirlik, Katja; Brummer, Tilman; Zeiser, Robert
- Abstract
Patients with BRAFV600E/K-driven melanoma respond to the BRAF inhibitor vemurafenib due to subsequent deactivation of the proliferative RAS/RAF/MEK/ERK pathway. In BRAF WT cells and those with mutations that activate or result in high levels of the BRAF activator RAS, BRAF inhibition can lead to ERK activation, resulting in tumorigenic transformation. We describe a patient with malignant melanoma who developed chronic lymphocytic leukemia (CLL) in the absence of RAS mutations during vemurafenib treatment. BRAF inhibition promoted patient CLL proliferation in culture and in murine xenografts and activated MEK/ERK in primary CLL cells from additional patients. BRAF inhibitor-driven ERK activity and CLL proliferation required B cell antigen receptor (BCR) activation, as inhibition of the BCR-proximal spleen tyrosine kinase (SYK) reversed ERK hyperactivation and proliferation of CLL cells from multiple patients, while inhibition of the BCR-distal Bruton tyrosine kinase had no effect. Additionally, the RAS-GTP/RAS ratio in primary CLL cells exposed to vemurafenib was reduced upon SYK inhibition. BRAF inhibition increased mortality and CLL expansion in mice harboring CLL xenografts; however, SYK or MEK inhibition prevented CLL proliferation and increased animal survival. Together, these results suggest that BRAF inhibitors promote B cell malignancies in the absence of obvious mutations in RAS or other receptor tyrosine kinases and provide a rationale for combined BRAF/MEK or BRAF/SYK inhibition.
- Subjects
ANTINEOPLASTIC agents; CELL lines; CELL physiology; CELLULAR signal transduction; CHRONIC lymphocytic leukemia; COMPARATIVE studies; RESEARCH methodology; MEDICAL cooperation; MELANOMA; GENETIC mutation; PHOSPHORYLATION; PROTEIN-tyrosine kinases; PROTEINS; RESEARCH; SKIN tumors; SULFONAMIDES; TRANSFERASES; EVALUATION research; TREATMENT effectiveness; SIGNAL peptides; INDOLE compounds; CHEMICAL inhibitors; THERAPEUTICS
- Publication
Journal of Clinical Investigation, 2014, Vol 124, Issue 11, p5074
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI76539