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Int J Mol Sci. 2018 Mar 23;19(4). pii: E969. doi: 10.3390/ijms19040969.

Preclinical Evaluation of Vemurafenib as Therapy for BRAFV600E Mutated Sarcomas.

Author information

1
Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, 0379 Oslo, Norway. sarina.gouravan@rr-research.no.
2
Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, 0379 Oslo, Norway. Leonardo.A.Meza-Zepeda@rr-research.no.
3
Genomics Core Facility, Department of Core facility, Institute for Cancer Research, Oslo University Hospital, 0379 Oslo, Norway. Leonardo.A.Meza-Zepeda@rr-research.no.
4
Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, 0379 Oslo, Norway. ola.myklebost@uib.no.
5
Department of Clinical Science, University of Bergen, Bergen, Norway. ola.myklebost@uib.no.
6
Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, 0379 Oslo, Norway. evaped@rr-research.no.
7
Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, 0379 Oslo, Norway. else.munthe@rr-research.no.

Abstract

The BRAFV600E mutation, which in melanoma is targetable with vemurafenib, is also found in sarcomas and we here evaluate the therapeutic potential in sarcoma cell lines.

METHODS:

Four sarcoma cell lines harboring the BRAFV600E mutation, representing liposarcomas (SA-4 and SW872), Ewing sarcoma (A673) and atypical synovial sarcoma (SW982), were treated with vemurafenib and the effects on cell growth, apoptosis, cell cycle progression and cell signaling were determined.

RESULTS:

Vemurafenib induced a strong cytostatic effect in SA-4 cells, mainly due to cell cycle arrest, whereas only moderate levels of apoptosis were observed. However, a high dose was required compared to BRAFV600E mutated melanoma cells, and removal of vemurafenib demonstrated that the continuous presence of drug was required for sustained growth inhibition. A limited growth inhibition was observed in the other three cell lines. Protein analyses demonstrated reduced phosphorylation of ERK during treatment with vemurafenib in all the four sarcoma cell lines confirming that the MAPK pathway is active in these cell lines, and that the pathway can be inhibited by vemurafenib, but also that these cells can proliferate despite this.

CONCLUSIONS:

These findings indicate that vemurafenib alone would not be an efficient therapy against BRAFV600E mutated sarcomas. However, further investigations of combination with other drugs are warranted.

KEYWORDS:

BRAF; drug repurposing; precision medicine

PMID:
29570692
PMCID:
PMC5979358
DOI:
10.3390/ijms19040969
[Indexed for MEDLINE]
Free PMC Article

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