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BRAF inhibitor–associated ERK activation drives development of chronic lymphocytic leukemia
Niuscha Yaktapour, … , Tilman Brummer, Robert Zeiser
Niuscha Yaktapour, … , Tilman Brummer, Robert Zeiser
Published October 20, 2014
Citation Information: J Clin Invest. 2014;124(11):5074-5084. https://doi.org/10.1172/JCI76539.
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Research Article Article has an altmetric score of 7

BRAF inhibitor–associated ERK activation drives development of chronic lymphocytic leukemia

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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.

Authors

Niuscha Yaktapour, Frank Meiss, Justin Mastroianni, Thorsten Zenz, Hana Andrlova, Nimitha R. Mathew, Rainer Claus, Barbara Hutter, Stefan Fröhling, Benedikt Brors, Dietmar Pfeifer, Milena Pantic, Ingrid Bartsch, Timo S. Spehl, Philipp T. Meyer, Justus Duyster, Katja Zirlik, Tilman Brummer, Robert Zeiser

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Figure 3

BRAF inhibition increases ERK phosphorylation and CLL proliferation in vivo, which can be reverted by SYK inhibition.

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BRAF inhibition increases ERK phosphorylation and CLL proliferation in v...
Highly purified (>97%) CD19+CD5+ cells (CLL) obtained from the patient were exposed to dabrafenib (6 μM) and R406 at increasing concentrations, as indicated, or DMSO as control. (A) A representative Western blot is shown. The experiment was performed twice with similar results. The pERK/tERK ratios (B) and the pSYK/tSYK ratios (C) are shown for the indicated conditions. (D) The patient’s CLL cells were exposed to dabrafenib, vemurafenib, R406, or DMSO as control at the indicated concentrations, and the resulting Western blot and the RAS-GTP/tRAS ratios are shown. One of 3 independent experiments with similar results is shown. (E) The amounts of CLL cells in the peripheral blood of Rag2–/–γC–/– mice on day 7 relative to treatment starting with vemurafenib (24 mg/kg/d) alone or vemurafenib and fostamatinib (60 mg/kg/d) are shown. On day 0, 2.5 × 107 patient-derived CD19+CD5+ cells were injected i.p. and i.v. (F) The survival of the Rag2–/–γC–/– mice treated as described in E is shown (P = 0.0001). Data from 2 experiments were pooled.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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