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在体外，达拉非尼和曲美替尼通过抑制BRAF突变黑色素瘤细胞中的组织因子来延长凝血时间。

Dabrafenib and Trametinib prolong coagulation through the inhibition of tissue factor in BRAF mutated melanoma cells in vitro.

作者信息

Scatena Cristian, Franceschi Sara, Franzini Maria, Sanguinetti Chiara, Romiti Nadia, Caponi Laura, Mandalà Mario, Mazzanti Chiara Maria, Naccarato Antonio Giuseppe

机构信息

1Division of Surgical Pathology, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 57, 56126 Pisa, Italy.

Fondazione Pisana per la Scienza, Pisa, Italy.

出版信息

Cancer Cell Int. 2019 Aug 28;19:223. doi: 10.1186/s12935-019-0938-3. eCollection 2019.

DOI:10.1186/s12935-019-0938-3
PMID:31467489
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6712666/
Abstract

BACKGROUND

Neoplastic cells promote a hypercoagulable state by the expression of cell surface proteins, such as tissue factor. In BRAF mutated melanoma patients upon BRAF inhibitors, a hypercoagulable state correlates with prognosis, while a down-regulation of the hemostatic parameters is observed in patients responders as compared to non responders. The present study was intended to better clarify the strict relationship between coagulation mediators and target therapy in melanoma.

METHODS

The expression of tissue factor was investigated after the treatment with the BRAF inhibitor Dabrafenib and the MEK inhibitor Trametinib in the BRAF mutated melanoma cell lines A-375 and SK-MEL-28, together with its ability to activate the coagulation cascade.

RESULTS

Dabrafenib and Trametinib caused the down-regulation of TF in both cell lines A-375 and SK-MEL-28. For the cell line A-375 the effect was evident both at RNA and procoagulant activity; for the cell line SK-MEL-28 only at RNA level without any variation of the protein. Interestingly, when in contact with plasma deficient of factor VII, both cell lines were not able to activate the coagulation cascade.

CONCLUSIONS

The present study provides the first in vitro observation that tissue factor expressed in melanoma cells may contribute to the modulation of the coagulation state of patients in the treatment with BRAF inhibitors.

摘要

背景

肿瘤细胞通过表达细胞表面蛋白（如组织因子）促进高凝状态。在接受BRAF抑制剂治疗的BRAF突变型黑色素瘤患者中，高凝状态与预后相关，与无反应者相比，有反应的患者止血参数下调。本研究旨在更好地阐明黑色素瘤中凝血介质与靶向治疗之间的紧密关系。

方法

在用BRAF抑制剂达拉非尼和MEK抑制剂曲美替尼处理BRAF突变的黑色素瘤细胞系A-375和SK-MEL-28后，研究组织因子的表达及其激活凝血级联反应的能力。

结果

达拉非尼和曲美替尼导致A-375和SK-MEL-28这两种细胞系中TF下调。对于A-375细胞系，在RNA和促凝活性方面均有明显效果；对于SK-MEL-28细胞系，仅在RNA水平有变化，而蛋白质无任何变化。有趣的是，当与缺乏因子VII的血浆接触时，两种细胞系均无法激活凝血级联反应。

结论

本研究首次提供体外观察结果，表明黑色素瘤细胞中表达的组织因子可能在BRAF抑制剂治疗中有助于调节患者的凝血状态。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0700/6712666/22362aba7288/12935_2019_938_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0700/6712666/754d01c038a0/12935_2019_938_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0700/6712666/4dc00e9126e1/12935_2019_938_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0700/6712666/b7c8434de1f0/12935_2019_938_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0700/6712666/0d939873274d/12935_2019_938_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0700/6712666/22362aba7288/12935_2019_938_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0700/6712666/754d01c038a0/12935_2019_938_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0700/6712666/4dc00e9126e1/12935_2019_938_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0700/6712666/b7c8434de1f0/12935_2019_938_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0700/6712666/0d939873274d/12935_2019_938_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0700/6712666/22362aba7288/12935_2019_938_Fig5_HTML.jpg

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