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.

中文翻译：

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Rigosertib 在 RAS 驱动的横纹肌肉瘤和神经母细胞瘤中诱导有丝分裂停滞和细胞凋亡

尽管进行了多模式治疗，但复发的小儿横纹肌肉瘤 (RMS) 和神经母细胞瘤 (NB) 的预后较差。此外，目前对这些癌症的治疗标准包括具有严重毒性特征的长春花生物碱，进一步强调了对这些恶性肿瘤新疗法的需求。在这里，我们展示了小分子 rigosertib 通过在有丝分裂中阻止细胞来抑制 RMS 和 NB 细胞系的生长，从而导致细胞死亡。我们的数据表明，rigosertib 与长春花生物碱一样，主要通过干扰有丝分裂纺锤体组装来发挥其作用。虽然 rigosertib 具有抑制致癌 RAS 信号传导的能力，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 通路来诱导细胞死亡。然而，rigosertib 和对 RAS 突变肿瘤有效的 MEK 抑制剂曲美替尼的组合协同抑制 RMS 细胞系的生长，为联合治疗提供了新途径。重要的是，rigosertib 治疗延缓肿瘤生长并延长 RMS 异种移植模型的存活时间。总之，rigosertib 通过其对有丝分裂纺锤体的影响，代表了 RMS 的潜在治疗方法。