Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, 0379 Oslo, Norway.
Genomics Core Facility, Department of Core facility, Institute for Cancer Research, Oslo University Hospital, 0379 Oslo, Norway.
Int J Mol Sci. 2018 Mar 23;19(4):969. doi: 10.3390/ijms19040969.
The BRAF mutation, which in melanoma is targetable with vemurafenib, is also found in sarcomas and we here evaluate the therapeutic potential in sarcoma cell lines.
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.
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 BRAF 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.
These findings indicate that vemurafenib alone would not be an efficient therapy against BRAF mutated sarcomas. However, further investigations of combination with other drugs are warranted.
BRAF 突变在黑色素瘤中可被 vemurafenib 靶向，也存在于肉瘤中，我们在此评估肉瘤细胞系中的治疗潜力。
四种携带 BRAFV600E 突变的肉瘤细胞系，代表脂肪肉瘤（SA-4 和 SW872）、尤文肉瘤（A673）和非典型滑膜肉瘤（SW982），用 vemurafenib 处理，并确定对细胞生长、凋亡、细胞周期进程和细胞信号的影响。
vemurafenib 在 SA-4 细胞中诱导强烈的细胞生长抑制作用，主要是由于细胞周期停滞，而仅观察到中度水平的凋亡。然而，与 BRAF 突变的黑色素瘤细胞相比，需要更高的剂量，并且在去除 vemurafenib 后，证明持续存在药物是持续生长抑制所必需的。在其他三种细胞系中观察到有限的生长抑制。蛋白分析表明，在所有四种肉瘤细胞系中，vemurafenib 治疗期间 ERK 的磷酸化减少，证实 MAPK 通路在这些细胞系中是活跃的，并且该通路可被 vemurafenib 抑制，但这些细胞仍可增殖。
这些发现表明，vemurafenib 单独治疗 BRAF 突变的肉瘤效果不佳。然而，需要进一步研究与其他药物的联合治疗。
