EGAGenomicsIllumina HiSeq 2500Otherhttps://ega-archive.org/studies/EGAS00001000948EGAEGA study EGAS00001000948Chronic lymphocytic leukemia driven by paradoxical ERK activation during BRAF inhibitor treatmentCooperative activity of BRAF F595L and mutant HRAS in histiocytic sarcoma provides new insights into oncogenic BRAF signalingrestrictedEGAPatients 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.BRAF inhibitor-associated ERK activation drives development of chronic lymphocytic leukemia.Yaktapour Niuscha N, Meiss Frank F, Mastroianni Justin J, Zenz Thorsten T, Andrlova Hana H, Mathew Nimitha R NR, Claus Rainer R, Hutter Barbara B, Fröhling Stefan S, Brors Benedikt B, Pfeifer Dietmar D, Pantic Milena M, Bartsch Ingrid I, Spehl Timo S TS, Meyer Philipp T PT, Duyster Justus J, Zirlik Katja K, Brummer Tilman T, Zeiser Robert RfalseDKFZ-HIPO Project H021/NCT MASTERClinical genome and transcriptome sequencing in younger adults with advanced-stage cancer across all histologies: DKFZ-HIPO Project H021 (http://www.hipo-heidelberg.org/hipo2/index.php/menu-item-2/32-021-prospective-genetic-characterization-of-tumors-from-individual-patients-of-special-interest) / NCT MASTER (http://www.nct-heidelberg.de/forschung/nct-master.html)2017-07-26 15:39:26EGAS00001000948960625329694EGAD00001000997EGAD00001001384EGAC00001000452