Department of Pediatrics, Division of Hematology-Oncology, University of California San Diego, La Jolla, CA, USA.
Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, USA.
Br J Cancer. 2020 Aug;123(4):568-579. doi: 10.1038/s41416-020-0905-8. Epub 2020 May 27.
Regorafenib is an inhibitor of multiple kinases with aberrant expression and activity in neuroblastoma tumours that have potential roles in neuroblastoma pathogenesis.
We evaluated neuroblastoma cells treated with regorafenib for cell viability and confluence, and analysed treated cells for apoptosis and cell cycle progression. We evaluated the efficacy of regorafenib in vivo using an orthotopic xenograft model. We evaluated regorafenib-mediated inhibition of kinase targets and performed reverse-phase protein array (RPPA) analysis of neuroblastoma cells treated with regorafenib. Lastly, we evaluated the efficacy and effects of the combination of regorafenib and 13-cis-retinoic acid on intracellular signalling.
Regorafenib treatment resulted in reduced neuroblastoma cell viability and confluence, with both induction of apoptosis and of cell cycle arrest. Regorafenib treatment inhibits known receptor tyrosine kinase targets RET and PDGFRβ and intracellular signalling through the RAS/MAPK, PI3K/Akt/mTOR and Fos/Jun pathways. Regorafenib is effective against neuroblastoma tumours in vivo, and the combination of regorafenib and 13-cis-retinoic acid demonstrates enhanced efficacy compared with regorafenib alone.
The effects of regorafenib on multiple intracellular signalling pathways and the potential additional efficacy when combined with 13-cis-retinoic acid represent opportunities to develop treatment regimens incorporating regorafenib for children with neuroblastoma.
regorafenib 是一种多激酶抑制剂，在神经母细胞瘤肿瘤中表达和活性异常，这些激酶在神经母细胞瘤发病机制中具有潜在作用。
我们评估了用 regorafenib 处理的神经母细胞瘤细胞的细胞活力和汇合度，并分析了处理后的细胞凋亡和细胞周期进展。我们使用原位异种移植模型评估了 regorafenib 的体内疗效。我们评估了 regorafenib 介导的激酶靶标抑制作用，并对用 regorafenib 处理的神经母细胞瘤细胞进行了反相蛋白阵列（RPPA）分析。最后，我们评估了 regorafenib 和 13-顺式维甲酸联合应用对细胞内信号转导的疗效和影响。
regorafenib 处理导致神经母细胞瘤细胞活力和汇合度降低，同时诱导细胞凋亡和细胞周期停滞。Regorafenib 治疗抑制已知的受体酪氨酸激酶靶标 RET 和 PDGFRβ 以及 RAS/MAPK、PI3K/Akt/mTOR 和 Fos/Jun 通路的细胞内信号转导。Regorafenib 在体内对神经母细胞瘤肿瘤有效，并且与单独使用 regorafenib 相比，regorafenib 和 13-顺式维甲酸的联合使用显示出增强的疗效。
Regorafenib 对多种细胞内信号通路的影响以及与 13-顺式维甲酸联合使用的潜在额外疗效为开发包含 regorafenib 的治疗方案提供了机会，用于治疗神经母细胞瘤患儿。
