Rigosertib Induces Mitotic Arrest and Apoptosis in RAS-Mutated Rhabdomyosarcoma and Neuroblastoma

Abstract

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.

Anti-tumor effects of rigosertib in high-risk neuroblastoma

“…Using a MYCN -amplified neuroblastoma PDX model, we observed that rigosertib can delay tumor growth in vivo , accompanied by an increase in apoptotic cells. This is in contrast to a recent study by Kowalczyk et al., in which rigosertib had no in vivo effects when using the conventional cell line SK-N-AS [18] . This discrepancy might reflect the fact that neuroblastoma is very heterogenous and drug responses can vary between patients.…”

“…Our finding that c-RAF (Ser338 phosphorylated) levels were unchanged by rigosertib might indicate that the decreases in pAKT (Ser473) and pERK1/2 (Thr202/204) were not caused by upstream blockage of RAS effectors but rather indirect effects due to other mechanisms like microtubule inhibition and cell cycle arrest. This is consistent with recent findings suggesting that rigosertib has tubulin-interacting effects rather than RAS signaling inhibitory effects in neuroblastoma [18] . It has also recently been reported that several cancer drugs in clinical trials do not function as previously thought but rather through off target-effects [33] , and this cannot be ruled out for rigosertib.…”

“…In a recent high-throughput drug screen, we identified rigosertib as a potential anti-neuroblastoma agent that displayed high selectivity towards tumor cells compared to healthy bone marrow-derived cells [17] . Recently, Kowalczyk and co-workers also showed that rigosertib can have anti-neuroblastoma effects in conventional in vitro neuroblastoma models [18] .…”

In Vitro Evaluation of Rigosertib Antitumoral and Radiosensitizing Effects against Human Cholangiocarcinoma Cells

“…Rig is a multi-kinase inhibitor that could be considered an alternative therapeutic option for different solid tumors and hematologic malignancies. Its efficacy against myelodysplastic syndrome, head and neck cancer, hepatocellular carcinoma, retinoblastoma, and glioblastoma has already been demonstrated [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ]. Moreover, on the website (July 2021) it is possible to highlight that Rigosertib is involved in various clinical trials.…”

Present and Future Perspective on PLK1 Inhibition in Cancer Treatment

“…Rigosertib (ON01910) is a benzyl sulfone analog that acts as a Ras mimetic, and non- ATP- competitive molecule inhibiting both PLK1 and PI3K ( 154 ). Rigosertib induces mitotic arrest in different cancer cells by inducing spindle abnormalities, cell cycle arrest and apoptosis ( 155 – 157 ).…”