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Extrinsic factors can mediate resistance to BRAF inhibition in central nervous system melanoma metastases

Seifert, Heike; Hirata, Eishu; Gore, Martin; Khabra, Komel; Messiou, Christina; Larkin, James; Sahai, Erik (2016). Extrinsic factors can mediate resistance to BRAF inhibition in central nervous system melanoma metastases. Pigment Cell & Melanoma Research, 29(1):92-100.

Abstract

Here, we retrospectively review imaging of 68 consecutive unselected patients with BRAF V600-mutant metastatic melanoma for organ-specific response and progression on vemurafenib. Complete or partial responses were less often seen in the central nervous system (CNS) (36%) and bone (16%) compared to lung (89%), subcutaneous (83%), spleen (71%), liver (85%) and lymph nodes/soft tissue (83%), P < 0.001. CNS was also the most common site of progression. Based on this, we tested in vitro the efficacy of the BRAF inhibitors PLX4720 and dabrafenib in the presence of cerebrospinal fluid (CSF). Exogenous CSF dramatically reduced cell death in response to both BRAF inhibitors. Effective cell killing was restored by co-administration of a PI-3 kinase inhibitor. We conclude that the efficacy of vemurafenib is variable in different organs with CNS being particularly prone to resistance. Extrinsic factors, such as ERK- and PI3K-activating factors in CSF, may mediate BRAF inhibitor resistance in the CNS.

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Oncology and Hematology
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Health Sciences > Oncology
Life Sciences > General Biochemistry, Genetics and Molecular Biology
Health Sciences > Dermatology
Language:German
Date:January 2016
Deposited On:12 Jan 2017 13:49
Last Modified:16 Oct 2024 01:38
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:1755-1471
OA Status:Hybrid
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1111/pcmr.12424
PubMed ID:26414886
Project Information:
  • Funder: FP7
  • Grant ID: 329047
  • Project Title: IMAGEMELTHERAPYLRI - Single cell level intravital imaging of response, tolerance, and resistance to targeted therapies
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  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)

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