期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 124, 期 11, 页码 5074-5084出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI76539
关键词
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资金
- Deutsche Forschungsgemeinschaft (DFG), Germany [DFG ZE 872/3-1, SFB 850]
- Excellence Initiative of the German Federal Government
- Excellence Initiative of the German State Government
- DFG [BR3662/1-1, BR3662/2-1]
- Mildred-Scheel Professorship of the Dt. Krebshilfe
- Deutsches Konsortium fur Translationale Krebsforschung (DKTK)
- German Cancer Aid (Max Eder stipend) [DKH 110461]
- [EXC 294 BIOSS]
Patients with BRAFV(600E/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.
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