Dabrafenib and Trametinib prolong coagulation through the inhibition of tissue factor in BRAFv600e mutated melanoma cells in vitro

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

doi:10.1186/s12935-019-0938-3

Dabrafenib and Trametinib prolong coagulation through the inhibition of tissue factor in BRAF^v600e mutated melanoma cells in vitro

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

Affiliations

¹ 1Division of Surgical Pathology, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 57, 56126 Pisa, Italy.
² Fondazione Pisana per la Scienza, Pisa, Italy.
³ 3Division of Clinical Pathology, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
⁴ Unit of Medical Oncology, Department of Oncology and Haematology, Papa Giovanni XXIII Cancer Center Hospital, Bergamo, Italy.

^# Contributed equally.

Abstract

Background: Neoplastic cells promote a hypercoagulable state by the expression of cell surface proteins, such as tissue factor. In BRAF^v600 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^v600e 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.

Keywords: Coagulation; Dabrafenib; Melanoma; Raf/MEK/ERK pathway; Tissue factor; Trametinib.