Background/Objectives: Plexiform neurofibromas (pNFs) are one of the cardinal presentations of NF1 patients, often arising during early childhood. Since selumetinib was approved by the FDA in 2020, the long-term side effects and various responses of mitogen-activated protein kinase inhibitors (MEKi) in pediatric patients necessitate a new strategy. We propose that combining selumetinib with heat shock protein 90 inhibitors (HSP90i) can enhance the inhibitory effects as well as reduce the dosage of selumetinib in combination. We validated the synergistic effects and the significantly improved treatment effects of the combination of selumetinib and HSP90i in pNFs.Methods: We used drug screen data mining to predict the combination of selumetinib and HSP90i. Using cell lines and in vivo mouse models for pNFs, we tested a series of combinations with different concentrations. We validated the in vivo inhibitory effects using the transplanted tumors fromDhhCreNf1f/fmouse models.Results: We demonstrated that combining selumetinib and SNX-2112 or retaspimycin can achieve better tumor inhibition with synergistic effects. The combination significantly delays the progression of mouse pNFs.Conclusions: The combination of selumetinib and HSP90i has significant synergistic effects, provides therapeutic inhibitor effects, and reduces the selumetinib dosage in combination.
背景/目的：丛状神经纤维瘤（pNFs）是神经纤维瘤病1型（NF1）患者的主要临床表现之一，常于儿童早期发病。自2020年司美替尼获美国食品药品监督管理局批准以来，丝裂原活化蛋白激酶抑制剂（MEKi）在儿科患者中长期副作用及个体疗效差异问题亟待新的治疗策略。我们提出将司美替尼与热休克蛋白90抑制剂（HSP90i）联用，以期增强抑制效果并降低联合用药中司美替尼的剂量。本研究验证了司美替尼与HSP90i联用在pNFs治疗中的协同效应及显著提升的疗效。 方法：通过药物筛选数据挖掘预测司美替尼与HSP90i的联合用药方案。采用pNFs细胞系及小鼠体内模型，测试不同浓度组合方案。利用DhhCreNf1f/f小鼠模型的移植瘤验证体内抑制效果。 结果：研究表明，司美替尼与SNX-2112或瑞他霉素联用可通过协同效应实现更优的肿瘤抑制效果。该联合治疗方案显著延缓了小鼠pNFs的疾病进展。 结论：司美替尼与HSP90i联用具有显著协同效应，既能增强治疗抑制作用，又可降低联合用药中司美替尼的剂量需求。
肿瘤(癌症)患者之家