Inducing Mitotic Catastrophe as a Therapeutic Approach to Improve Outcomes in Ewing Sarcoma.

Creator(s)

Soumya M. Turaga
Vikalp Vishwakarma
Stacey L. Hembruff
Benjamin K. Gibbs
Priya Sabu
Rajni V. Puri
Harsh B. Pathak
Glenson Samuel, Children's Mercy Kansas CityFollow
Andrew K. Godwin

Document Type

Article

Publication Date

10-10-2023

Identifier

DOI: 10.3390/cancers15204911; PMCID: PMC10605681

Abstract

Ewing sarcoma (EWS) is an aggressive pediatric malignancy of the bone and soft tissues in need of novel therapeutic options. To identify potential therapeutic targets, we focused on essential biological pathways that are upregulated by EWS-FLI1, the primary oncogenic driver of EWS, including mitotic proteins such as Aurora kinase A (AURKA) and kinesin family member 15 (KIF15) and its binding partner, targeting protein for Xklp2 (TPX2). KIF15/TPX2 cooperates with KIF11, a key mitotic kinesin essential for mitotic spindle orientation. Given the lack of clinical-grade KIF15/TPX2 inhibitors, we chose to target KIF11 (using SB-743921) in combination with AURKA (using VIC-1911) given that phosphorylation of KIF15S1169 by Aurora A is required for its targeting to the spindle. In vitro, the drug combination demonstrated strong synergy (Bliss score ≥ 10) at nanomolar doses. Colony formation assay revealed significant reduction in plating efficiency (1-3%) and increased percentage accumulation of cells in the G2/M phase with the combination treatment (45-52%) upon cell cycle analysis, indicating mitotic arrest. In vivo studies in EWS xenograft mouse models showed significant tumor reduction and overall effectiveness: drug combination vs. vehicle control (p ≤ 0.01), SB-743921 (p ≤ 0.01) and VIC-1911 (p ≤ 0.05). Kaplan-Meier curves demonstrated superior overall survival with the combination compared to vehicle or monotherapy arms (p ≤ 0.0001).

Journal Title

Cancers (Basel)

Volume

15

Issue

20

Keywords

Aurora kinase A; Ewing sarcoma; SB-743921; VIC-1911; drug synergy; kinesin family member 11

Comments

Grants and funding

• n/a/Braden's Hope for Childhood Cancer
• n/a/Noah's Bandage
• GM130423/Kansas Institute for Precision Medicine
• n/a/KUMC Biomedical Training Research Fellowship

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

Publisher's Link: https://www.mdpi.com/2072-6694/15/20/4911

Recommended Citation

Turaga SM, Vishwakarma V, Hembruff SL, et al. Inducing Mitotic Catastrophe as a Therapeutic Approach to Improve Outcomes in Ewing Sarcoma. Cancers (Basel). 2023;15(20):4911. Published 2023 Oct 10. doi:10.3390/cancers15204911