背景:结节性硬化症(TSC)由TSC1/TSC2中的变体引起,导致哺乳动物雷帕霉素靶标(mTOR)复合物1的组成型激活。依维莫司疗法已被批准用于TSC,但是成功的变化是频繁的。最近,尾晚期神经元间祖细胞(CLIP)细胞被确定为TSC脑病理学的常见起源,例如室管膜下巨细胞星形细胞瘤(SEGA)和皮质块茎(CT)。Further,用阿法替尼靶向表皮生长因子受体(EGFR),在CLIP细胞中表达,减少脑TSC类器官中的细胞生长。然而,缺乏对临床患者数据的调查。
目的:EGFR在SEGA、CT和局灶性皮质发育不良(FCD)2B人脑标本,并研究其抑制作用是否可能是这些患者的潜在治疗干预措施。
方法:23个SEGA的脑标本,6个CT,通过免疫组织化学分析了20个FCD2Bs和17个对照,以表征EGFR的表达,细胞增殖(通过Mib1)和mTOR信号。在使用原发性患者来源细胞的基于细胞的测定中(CTn=1,FCD2Bn=1和SEGAn=4),观察阿法替尼和依维莫司对细胞增殖和细胞活力的影响。
结果:在SEGA的组织学切片中观察到EGFR过表达,CT和FCD2B患者。依维莫司和阿法替尼均降低原发性SEGA的增殖和活力,块茎和FCD2B细胞。
结论:我们的研究表明,EGFR抑制可能是SEGA和块茎的有效替代治疗选择,以及其他与mTOR相关的皮质发育畸形,包括FCD2B。
BACKGROUND: Tuberous sclerosis complex (
TSC) is caused by variants in TSC1/TSC2, leading to constitutive activation of the mammalian target of rapamycin (mTOR) complex 1. Therapy with everolimus has been approved for
TSC, but variations in success are frequent. Recently, caudal late interneuron progenitor (CLIP) cells were identified as a common origin of the
TSC brain pathologies such as subependymal giant cell astrocytomas (SEGA) and cortical tubers (CT). Further, targeting the epidermal growth factor receptor (EGFR) with afatinib, which is expressed in CLIP cells, reduces cell growth in cerebral
TSC organoids. However, investigation of clinical patient-derived data is lacking.
OBJECTIVE: Observation of EGFR expression in SEGA, CT and focal cortical dysplasia (FCD) 2B human brain specimen and investigation of whether its inhibition could be a potential therapeutic intervention for these patients.
METHODS: Brain specimens of 23 SEGAs, 6 CTs, 20 FCD2Bs and 17 controls were analysed via immunohistochemistry to characterise EGFR expression, cell proliferation (via Mib1) and mTOR signalling. In a cell-based assay using primary patient-derived cells (CT n = 1, FCD2B n = 1 and SEGA n = 4), the effects of afatinib and everolimus on cell proliferation and cell viability were observed.
RESULTS: EGFR overexpression was observed in histological sections of SEGA, CT and FCD2B patients. Both everolimus and afatinib decreased the proliferation and viability in primary SEGA, tuber and FCD2B cells.
CONCLUSIONS: Our study demonstrates that EGFR suppression might be an effective alternative treatment option for SEGAs and tubers, as well as other mTOR-associated malformations of cortical development, including FCD2B.