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

Soumya M Turaga; Vikalp Vishwakarma; Stacey L Hembruff; Benjamin K Gibbs; Priya Sabu; Rajni V Puri; Harsh B Pathak; Glenson Samuel; Andrew K Godwin

doi:10.20944/preprints202309.2164.v1

Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Version 1 : Received: 29 September 2023 / Approved: 30 September 2023 / Online: 30 September 2023 (08:26:49 CEST)

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), 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 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 percent accumulation of cells in 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).

Ewing sarcoma; drug synergy; Kinesin Family Member 11; Aurora Kinase A; SB-743921; and VIC-1911

Medicine and Pharmacology, Oncology and Oncogenics

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

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