Glinkina Kseniya, Groenewoud Arwin, Teunisse Amina F A S, Snaar-Jagalska B Ewa, Jochemsen Aart G
Department of Cell and Chemical Biology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
Department of Molecular Cell Biology, Institute of Biology, Leiden University, 2300 RC Leiden, The Netherlands.
Cancers (Basel). 2022 Jun 29;14(13):3186. doi: 10.3390/cancers14133186.
Currently, no systemic treatment is approved as the standard of care for metastatic uveal melanoma (UM). mTOR has been evaluated as a drug target in UM. However, one of the main limitations is dose reduction due to adverse effects. The combination of everolimus with another targeted agent would allow the reduction of the dose of a single drug, thus widening the therapeutic window. In our study, we aimed to identify a synergistic combination with everolimus in order to develop a novel treatment option for metastatic UM. We exploited CRISPR-Cas9 synthetic lethality screening technology to search for an efficient combination. and and several other genes were identified as hits in the screen. We investigated the effect of the combination of everolimus with the inhibitors targeting IGF1R and DNA-PKcs on the survival of UM cell lines. These combinations synergistically slowed down cell growth but did not induce apoptosis in UM cell lines. These combinations were tested on PDX UM in an in vivo model, but we could not detect tumor regression. However, we could find significant activity of the dual DNA-PKcs/mTOR inhibitor CC-115 on PDX UM in the in vivo model.
目前，尚无全身治疗被批准作为转移性葡萄膜黑色素瘤（UM）的标准治疗方案。mTOR已被评估为UM的药物靶点。然而，主要限制之一是由于不良反应导致剂量减少。依维莫司与另一种靶向药物联合使用将允许减少单一药物的剂量，从而拓宽治疗窗口。在我们的研究中，我们旨在确定与依维莫司的协同组合，以便为转移性UM开发一种新的治疗选择。我们利用CRISPR-Cas9合成致死筛选技术来寻找有效的组合。在筛选中，IGF1R和其他几个基因被确定为命中基因。我们研究了依维莫司与靶向IGF1R和DNA-PKcs的抑制剂联合使用对UM细胞系存活的影响。这些组合协同减缓了细胞生长，但未诱导UM细胞系凋亡。这些组合在体内模型的PDX UM上进行了测试，但我们未检测到肿瘤消退。然而，我们在体内模型中发现双DNA-PKcs/mTOR抑制剂CC-115对PDX UM具有显著活性。
