ArticleThe Journal of clinical investigation2014
BRAF inhibitor-associated ERK activation drives development of chronic lymphocytic leukemia.
Article in The Journal of clinical investigation, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
36 citing papers in PubMed, 65 citations in OpenAlex.
- Discovery of Cyclic Peptides Targeting the BRAF Dimer Interface as Dual Inhibitors.ACS pharmacology & translational science · 2026Article
- BRAF Alterations in Chronic Lymphocytic Leukemia: Genomic Landscape, Co-Mutation Patterns, and Clinical Relevance.Current hematologic malignancy reports · 2026Review
- Enzyme Is the Name-Adapter Is the Game.Cells · 2024Review
- Onco-immunomodulatory properties of pharmacological interference with RAS-RAF-MEK-ERK pathway hyperactivation.Frontiers in oncology · 2022Review
- High-throughput virtual screening and preclinical analysis identifies CB-1, a novel potent dual B-Raf/c-Raf inhibitor, effective against wild and mutant variants of B-Raf expression in colorectal carcinoma.Journal of computer-aided molecular design · 2021Article
- Wnt5a enhances proliferation of chronic lymphocytic leukemia and ERK1/2 phosphorylation via a ROR1/DOCK2-dependent mechanism.Leukemia · 2021Article
- MicroRNA-425 inhibits proliferation of chronic lymphocytic leukaemia cells through regulation of the Bruton's tyrosine kinase/phospholipase Cγ2 signalling pathway.Experimental and therapeutic medicine · 2020Article
- Targetable ERBB2 mutations identified in neurofibroma/schwannoma hybrid nerve sheath tumors.The Journal of clinical investigation · 2020Article
- Biology and Treatment of Hairy Cell Leukemia.Current treatment options in oncology · 2020Review
- Clinical considerations about the coexistence of melanoma and chronic lymphocytic leukemia in the era of targeted therapies, triggered by rare clinical scenarios. A case series and review of the literature.Therapeutic advances in medical oncology · 2020Article
- Vemurafenib acts as an aryl hydrocarbon receptor antagonist: Implications for inflammatory cutaneous adverse events.Allergy · 2019Article
- Article
- Design and Synthesis of Type-IV Inhibitors of BRAF Kinase That Block Dimerization and Overcome Paradoxical MEK/ERK Activation.Journal of medicinal chemistry · 2019Article
- Article
- [BRAF gene mutations in ameloblastic fibromas].Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences · 2019Article
- B-Raf deficiency impairs tumor initiation and progression in a murine breast cancer model.Oncogene · 2019Article
- Dissecting RAF Inhibitor Resistance by Structure-based Modeling Reveals Ways to Overcome Oncogenic RAS Signaling.Cell systems · 2018Article
- AZ304, a novel dual BRAF inhibitor, exerts anti-tumour effects in colorectal cancer independently of BRAF genetic status.British journal of cancer · 2018Article
- From somatic variants towards precision oncology: Evidence-driven reporting of treatment options in molecular tumor boards.Genome medicine · 2018Article
- Response and Resistance to Paradox-Breaking BRAF Inhibitor in MelanomasMolecular cancer therapeutics · 2018Article
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Authors and funding
19 authors at 6 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.