Preclinical Evaluation of Vemurafenib as Therapy for BRAFV600E Mutated Sarcomas

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.

Multifocal primary central nervous system Ewing sarcoma presenting with intracranial hemorrhage and leptomeningeal dissemination: illustrative case

“…Work performed by Gouravan et al targeted V600E BRAF mutations in sarcomas using vemurafenib. 31 Vemurafenib has previously been used to target melanoma with V600E BRAF mutations with a good response rate and prolonged progression-free survival, though similar results were not seen in colorectal cancer patients with the same mutation owing to rapid resistance. In this preclinical trial using four sarcoma lines, one of which was an ES, there was evidence of poor response to vemurafenib, suggesting that it may be an ineffective candidate for clinical application in sarcomas.…”

Transcriptomic analysis functionally maps the intrinsically disordered domain of EWS/FLI and reveals novel transcriptional dependencies for oncogenesis

“…The reason A673 cells are uniquely tolerant to loss of EWS/FLI remain poorly understood. These cells possess a V600E mutated BRAF, however, RNAi-mediated depletion of BRAF or treatment with vemurafenib shows limited impact on cell behavior [ 53 – 55 ]. Nonetheless, expanding the repertoire of robust systems to meaningfully interrogate the function of EWS/FLI remains an ongoing challenge for the field.…”

Case Report: Eighteen Month Relapse- Free Survival Following Radical Multidisciplinary Oncological Treatment in a 68-Year-Old Male Patient With Histiocytic Sarcoma

“…Based on these reports, targeted therapy with the MEK inhibitor cobimetinib might be a promising strategy with relapse free intervals for up to 1.5 years (12). In addition, there are specific BRAF inhibitors, such as vemurafenib (Zelboraf ® ), dabrafenib (Tafinlar ® ), and encorafenib (Braftovi ® ) which could be additional options for such patients in the future if mutation analysis is carried out at the time of surgery, and made part of ongoing treatment after the chemo-and radiation therapy and may extend life (13)(14)(15). However, randomized studies to test the possible efficacy of this treatment are lacking to date.…”