title: BRAF inhibitor-associated ERK activation drives development of chronic lymphocytic leukemia.
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.forename: Niuscha
authors.initials: N
authors.lastname: Yaktapour
authors.forename: Frank
authors.initials: F
authors.lastname: Meiss
authors.forename: Justin
authors.initials: J
authors.lastname: Mastroianni
authors.forename: Thorsten
authors.initials: T
authors.lastname: Zenz
authors.forename: Hana
authors.initials: H
authors.lastname: Andrlova
authors.forename: Nimitha R
authors.initials: NR
authors.lastname: Mathew
authors.forename: Rainer
authors.initials: R
authors.lastname: Claus
authors.forename: Barbara
authors.initials: B
authors.lastname: Hutter
authors.forename: Stefan
authors.initials: S
authors.lastname: Fröhling
authors.forename: Benedikt
authors.initials: B
authors.lastname: Brors
authors.forename: Dietmar
authors.initials: D
authors.lastname: Pfeifer
authors.forename: Milena
authors.initials: M
authors.lastname: Pantic
authors.forename: Ingrid
authors.initials: I
authors.lastname: Bartsch
authors.forename: Timo S
authors.initials: TS
authors.lastname: Spehl
authors.forename: Philipp T
authors.initials: PT
authors.lastname: Meyer
authors.forename: Justus
authors.initials: J
authors.lastname: Duyster
authors.forename: Katja
authors.initials: K
authors.lastname: Zirlik
authors.forename: Tilman
authors.initials: T
authors.lastname: Brummer
authors.forename: Robert
authors.initials: R
authors.lastname: Zeiser
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000009:adverse effects* / Q000627:therapeutic use; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000139:chemically induced / Q000000981:diagnostic imaging*; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics; D008875:Middle Aged; D020125:Mutation, Missense; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics; D011877:Radionuclide Imaging; D012878:Skin Neoplasms / Q000188:drug therapy / Q000235:genetics; D013449:Sulfonamides / Q000009:adverse effects* / Q000627:therapeutic use; D000072377:Syk Kinase; D016896:Treatment Outcome; D000077484:Vemurafenib
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D013449:Sulfonamides; D000077484:Vemurafenib; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases