National Cancer Institute, Bethesda, Maryland.
National Center for Advancing Translational Sciences, Rockville, Maryland.
Mol Cancer Ther. 2021 Feb;20(2):307-319. doi: 10.1158/1535-7163.MCT-20-0525. Epub 2020 Nov 6.
Relapsed pediatric rhabdomyosarcomas (RMS) and neuroblastomas (NBs) have a poor prognosis despite multimodality 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. Although 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.
复发性儿科横纹肌肉瘤（RMS）和神经母细胞瘤（NB）尽管采用多模式疗法，但预后仍然较差。此外，这些癌症的当前治疗标准包括长春花生物碱，其具有严重的毒性特征，进一步强调了这些恶性肿瘤需要新型治疗方法。在这里，我们表明小分子 rigosertib 通过将细胞阻滞在有丝分裂期中来抑制 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作用。尽管 rigosertib 具有抑制致癌性 RAS 信号的能力，但我们提供的证据表明，rigosertib 不会通过抑制 RAS 通路诱导 RAS 突变 RMS 和 NB 细胞死亡。然而，rigosertib 与 MEK 抑制剂 trametinib 的组合在 RAS 突变肿瘤中具有疗效，可协同抑制 RMS 细胞系的生长，这表明联合治疗有了新的途径。重要的是，rigosertib 治疗可延迟 RMS 异种移植模型中的肿瘤生长并延长生存期。总之，rigosertib 通过其对有丝分裂纺锤体的影响，代表了一种治疗 RMS 的潜在疗法。
