Background: Meningiomas represent ∼30% of primary central nervous system (CNS) tumors. Although advances in surgery and radiotherapy have significantly improved survival, there remains an important subset of patients whose tumors have more aggressive behavior and are refractory to conventional therapy. Recent advances in molecular genetics and epigenetics suggest that this aggressive behavior may be due to the deletion of the DNA repair and tumor suppressor gene, CHEK2, neurofibromatosis Type 2 (NF2) mutation on chromosome 22q12, and genetic abnormalities in multiple RTKs including FGFRs. Management of higher-grade meningiomas, such as anaplastic meningiomas (AM: WHO grade III), is truly challenging and there isn’t an established chemotherapy option. We investigate the effect of active multi tyrosine receptor kinase inhibitor Dovitinib at stopping AM cell growth in in vitro with either frequent codeletion or mutated CHEK2 and NF2 gene.

Methods: Treatment effects were assessed using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, western blot analysis, caspases assay, and DNA fragmentation assay.

Results: Treatment of CH157MN and IOMM-Lee cells with Dovitinib suppressed multiple angiokinases—mainly FGFRs, leading to suppression of downstream signaling by RAS–RAF–MAPK molecules and PI3K–AKT molecules which are involved in cell proliferation, cell survival, and tumor invasion. Furthermore, Dovitinib induced apoptosis via downregulation of survival proteins (Bcl-XL), and over-expression of apoptotic factors (Bax and caspase-3) regardless of CHEK2 and NF2 mutation status.

Conclusions: This study establishes the groundwork for the development of Dovitinib as a therapeutic agent for high-grade AM with either frequent codeletion or mutated CHEK2 and NF2, an avenue with high translational potential.

背景：脑膜瘤约占原发性中枢神经系统（CNS）肿瘤的30％。尽管外科手术和放射疗法的进步显着提高了生存率，但仍有一部分患者的肿瘤具有更强的侵袭性，并且对传统疗法无能为力。分子遗传学和表观遗传学的最新进展表明，这种攻击性行为可能是由于DNA修复和抑癌基因CHEK2的缺失所致，第22q12号染色体上出现2型神经纤维瘤病（NF2）突变，以及包括FGFR在内的多个RTK的遗传异常。高级别脑膜瘤的治疗，如间变性性脑膜瘤（AM：WHO III级），确实具有挑战性，目前尚无固定的化疗方案。我们调查了频繁的小写或突变的CHEK2和NF2基因在体外停止主动AM酪氨酸激酶抑制剂Dovitinib对AM细胞生长的影响。

方法：采用MTT（3-（4,5-二甲基噻唑-2-基）-2,5-二苯基四唑溴化物）测定，蛋白质印迹分析，胱天蛋白酶分析和DNA片段化分析评估治疗效果。

结果：用多维替尼处理CH157MN和IOMM-Lee细胞可抑制多种血管激酶-主要是FGFR，从而导致RAS-RAF-MAPK分子和PI3K-AKT分子抑制下游信号传导，这些信号参与细胞增殖，细胞存活和肿瘤侵袭。此外，无论CHEK2和NF2突变状态如何，多维替尼都通过下调生存蛋白（Bcl-XL）和凋亡因子（Bax和caspase-3）的表达来诱导凋亡。

结论：这项研究为多维替尼作为高频率AM的治疗药物奠定了基础，该药物具有频繁的代码缺失或CHEK2和NF2突变，这是一种具有高翻译潜力的途径。