Header

UZH-Logo

Maintenance Infos

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.

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.

Statistics

Altmetrics

Downloads

14 downloads since deposited on 12 Jan 2017
14 downloads since 12 months
Detailed statistics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Oncology
Dewey Decimal Classification:610 Medicine & health
Language:German
Date:January 2016
Deposited On:12 Jan 2017 13:49
Last Modified:21 Nov 2017 18:52
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:1755-1471
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1111/pcmr.12424
PubMed ID:26414886

Download

Download PDF  'Extrinsic factors can mediate resistance to BRAF inhibition in central nervous system melanoma metastases'.
Preview
Content: Published Version
Filetype: PDF
Size: 1MB
View at publisher
Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)