%0 Journal Article %1 Yaktapour2014 %A Yaktapour, Niuscha %A Meiss, Frank %A Mastroianni, Justin %A Zenz, Thorsten %A Andrlova, Hana %A Mathew, Nimitha R. %A Claus, Rainer %A Hutter, Barbara %A Fröhling, Stefan %A Brors, Benedikt %A Pfeifer, Dietmar %A Pantic, Milena %A Bartsch, Ingrid %A Spehl, Timo S. %A Meyer, Philipp T. %A Duyster, Justus %A Zirlik, Katja %A Brummer, Tilman %A Zeiser, Robert %D 2014 %J J Clin Invest %K ABI-DKFZ %N 11 %P 5074--5084 %R 10.1172/JCI76539 %T BRAF inhibitor-associated ERK activation drives development of chronic lymphocytic leukemia. %U http://dx.doi.org/10.1172/JCI76539 %V 124 %X 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.

@article{Yaktapour2014, __markedentry = {[bbrors:6]}, 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.}, added-at = {2015-06-29T14:32:37.000+0200}, author = {Yaktapour, Niuscha and Meiss, Frank and Mastroianni, Justin and Zenz, Thorsten and Andrlova, Hana and Mathew, Nimitha R. and Claus, Rainer and Hutter, Barbara and Fr{\"{o}}hling, Stefan and Brors, Benedikt and Pfeifer, Dietmar and Pantic, Milena and Bartsch, Ingrid and Spehl, Timo S. and Meyer, Philipp T. and Duyster, Justus and Zirlik, Katja and Brummer, Tilman and Zeiser, Robert}, biburl = {https://www.bibsonomy.org/bibtex/2d0c4771cb952799e26d9fa4993c6529c/juraeva}, doi = {10.1172/JCI76539}, interhash = {e5570fa3da0f1c81df9c8493a702c4db}, intrahash = {d0c4771cb952799e26d9fa4993c6529c}, journal = {J Clin Invest}, keywords = {ABI-DKFZ}, language = {eng}, medline-pst = {ppublish}, month = nov, number = 11, owner = {bbrors}, pages = {5074--5084}, pii = {76539}, pmid = {25329694}, timestamp = {2015-06-29T14:34:20.000+0200}, title = {BRAF inhibitor-associated ERK activation drives development of chronic lymphocytic leukemia.}, url = {http://dx.doi.org/10.1172/JCI76539}, volume = 124, year = 2014 }