Khan Sajjad, Aina Oluwatosin, Veneklasen Ximei, Edens Hannah, Alson Donia, Sun Li, Zayed Huda, Njoya Kimani, Sun Daochun
Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Cancers (Basel). 2025 Jul 16;17(14):2359. doi: 10.3390/cancers17142359.
: 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. : 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 from mouse models. : 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. : The combination of selumetinib and HSP90i has significant synergistic effects, provides therapeutic inhibitor effects, and reduces the selumetinib dosage in combination.
丛状神经纤维瘤（pNFs）是1型神经纤维瘤病（NF1）患者的主要临床表现之一，通常在儿童早期出现。自2020年塞鲁替尼被美国食品药品监督管理局（FDA）批准以来，丝裂原活化蛋白激酶抑制剂（MEKi）在儿科患者中的长期副作用和各种反应需要一种新的策略。我们提出，将塞鲁替尼与热休克蛋白90抑制剂（HSP90i）联合使用可以增强抑制作用，并降低联合使用时塞鲁替尼的剂量。我们验证了塞鲁替尼和HSP90i联合使用在pNFs中的协同作用和显著改善的治疗效果。：我们使用药物筛选数据挖掘来预测塞鲁替尼和HSP90i的联合使用。使用pNFs的细胞系和体内小鼠模型，我们测试了一系列不同浓度的联合使用。我们使用来自小鼠模型的移植肿瘤验证了体内抑制作用。：我们证明，将塞鲁替尼与SNX-2112或瑞他司匹林联合使用可以实现更好的肿瘤抑制，并具有协同作用。这种联合显著延缓了小鼠pNFs的进展。：塞鲁替尼和HSP90i联合使用具有显著的协同作用，提供治疗性抑制作用，并降低联合使用时塞鲁替尼的剂量。
