Rigosertib Induces Mitotic Arrest and Apoptosis in RAS-Mutated Rhabdomyosarcoma and Neuroblastoma.
Rigosertib Induces Mitotic Arrest and Apoptosis in RAS-Mutated Rhabdomyosarcoma and Neuroblastoma.
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Rigosertib诱导RAS突变型横纹肌肉瘤和神经母细胞瘤的有丝分裂阻滞和细胞凋亡。
DOI：
10.1158/1535-7163.mct-20-0525
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发表时间：
2021-03
影响因子：
5.7
通讯作者：
Yohe ME
中科院分区：
文献类型：
--
作者：
Kowalczyk JT;Wan X;Hernandez ER;Luo R;Lyons GC;Wilson KM;Gallardo DC;Isanogle KA;Robinson CM;Mendoza A;Heske CM;Chen JQ;Luo X;Kelly AE;Difilippantinio S;Robey RW;Thomas CJ;Sackett DL;Morrison DK;Randazzo PA;Jenkins LMM;Yohe ME
复发的儿童横纹肌肉瘤(RMS)和神经母细胞瘤(NB)预后较差，尽管采取了多种治疗方法。此外，目前治疗这些癌症的标准包括具有严重毒性的长春花碱，进一步强调了对这些恶性肿瘤进行新疗法的必要性。在这里，我们展示了小分子rigosertib通过阻止细胞有丝分裂而抑制RMS和NB细胞的生长，从而导致细胞死亡。我们的数据表明，rigosertib和长春花碱一样，主要通过干扰有丝分裂纺锤体组装来发挥作用。虽然rigosertib有能力抑制致癌的RAS信号，但我们提供的证据表明，rigosertib不会通过抑制RAS突变的RMS和NB细胞中的RAS途径而诱导细胞死亡。然而，rigosertib和MEK抑制剂曲美替尼的组合对RAS突变的肿瘤有效，协同抑制RMS细胞系的生长，为联合治疗提供了一条新的途径。重要的是，在RMS的异种移植模型中，rigosertib治疗延缓了肿瘤的生长并延长了生存时间。总之，rigosertib通过对有丝分裂纺锤体的影响，代表了一种治疗RMS的潜在方法。
Relapsed pediatric rhabdomyosarcomas (RMS) and neuroblastomas (NB) have a poor prognosis despite multi-modality therapy. In addition, the current standard of care for these cancers includes vinca alkaloids that have severe toxicity profiles, further underscoring the need for novel therapies for these malignancies. Here, we show that the small molecule rigosertib inhibits the growth of RMS and NB cell lines by arresting cells in mitosis, which leads to cell death. Our data indicate that rigosertib, like the vinca alkaloids, exerts its effects mainly by interfering with mitotic spindle assembly. While rigosertib has the ability to inhibit oncogenic RAS signaling, we provide evidence that rigosertib does not induce cell death through inhibition of the RAS pathway in RAS-mutated RMS and NB cells. However, the combination of rigosertib and the MEK inhibitor trametinib, which has efficacy in RAS-mutated tumors, synergistically inhibits the growth of an RMS cell line, suggesting a new avenue for combination therapy. Importantly, rigosertib treatment delays tumor growth and prolongs survival in a xenograft model of RMS. In conclusion, rigosertib, through its impact on the mitotic spindle, represents a potential therapeutic for RMS.
影响因子：
8.8
作者：
Cocker HA;Hobbs SM;Tiffin N;Pritchard-Jones K;Pinkerton CR;Kelland LR
通讯作者：
Kelland LR