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Published on: April 11, 2018
Preclinical Evaluation of Vemurafenib as Therapy for BRAFV600E Mutated Sarcomas
Sarina Gouravan1, Leonardo A Meza-Zepeda2,3, Ola Myklebost4,5
1Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, 0379 Oslo, Norway. sarina.gouravan@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.
Insights
Vemurafenib shows limited efficacy as a standalone treatment for BRAF V600E mutated sarcomas, necessitating further research into combination therapies for improved outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- The BRAF V600E mutation, a targetable driver in melanoma, is also present in various sarcoma subtypes.
- Understanding the therapeutic potential of BRAF inhibitors in sarcomas is crucial for expanding treatment options.
Purpose of the Study:
- To evaluate the efficacy of vemurafenib, a BRAF inhibitor, in preclinical sarcoma models harboring the BRAF V600E mutation.
- To investigate the effects of vemurafenib on cell growth, apoptosis, cell cycle, and MAPK signaling in these sarcoma cell lines.
Main Methods:
- Four BRAF V600E-mutated sarcoma cell lines (liposarcoma, Ewing sarcoma, synovial sarcoma) were treated with vemurafenib.
- Assays included cell growth, apoptosis, cell cycle progression, and Western blot analysis for MAPK pathway signaling (ERK phosphorylation).
Main Results:
- Vemurafenib demonstrated significant cytostatic effects in one liposarcoma cell line (SA-4) via cell cycle arrest, but required high doses and continuous exposure.
- Limited growth inhibition was observed in the other three cell lines, despite confirmed MAPK pathway inhibition.
- ERK phosphorylation was reduced in all cell lines, indicating pathway inhibition, yet proliferation persisted.
Conclusions:
- Vemurafenib monotherapy is unlikely to be an effective treatment for BRAF V600E-mutated sarcomas.
- Combination therapies involving vemurafenib warrant further investigation for potential synergistic effects in sarcoma treatment.
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