Mitochondrial Dysfunction Is a Driver of SP-2509 Drug Resistance in Ewing Sarcoma

Tokarsky, EJ; Crow, JC; Guenther, LM; Sherman, J; Taslim, C; Alexe, G; Pishas, KI; Rask, G; Justis, BS; Kasumova, A; Stegmaier, K; Lessnick, SL; Theisen, ER

Author(s): Tokarsky, EJ; Crow, JC; Guenther, LM; Sherman, J; Taslim, C; Alexe, G; Pishas, KI; Rask, G; Justis, BS; Kasumova, A; Stegmaier, K; Lessnick, SL; Theisen, ER;
Details: Publication Year 2022-07-06,Volume 20,Issue #7,Page 1035-1046
Journal Title: Molecular Cancer Research
Publication Type: Research article
Abstract: Expression of the fusion oncoprotein EWS/FLI causes Ewing sarcoma, an aggressive pediatric tumor characterized by widespread epigenetic deregulation. These epigenetic changes are targeted by novel lysine-specific demethylase-1 (LSD1) inhibitors, which are currently in early-phase clinical trials. Single-agent-targeted therapy often induces resistance, and successful clinical development requires knowledge of resistance mechanisms, enabling the design of effective combination strategies. Here, we used a genome-scale CRISPR-Cas9 loss-of-function screen to identify genes whose knockout (KO) conferred resistance to the LSD1 inhibitor SP-2509 in Ewing sarcoma cell lines. Multiple genes required for mitochondrial electron transport chain (ETC) complexes III and IV function were hits in our screen. We validated this finding using genetic and chemical approaches, including CRISPR KO, ETC inhibitors, and mitochondrial depletion. Further global transcriptional profiling revealed that altered complex III/IV function disrupted the oncogenic program mediated by EWS/FLI and LSD1 and blunted the transcriptomic response to SP-2509. IMPLICATIONS: These findings demonstrate that mitochondrial dysfunction modulates SP-2509 efficacy and suggest that new therapeutic strategies combining LSD1 with agents that prevent mitochondrial dysfunction may benefit patients with this aggressive malignancy.
Keywords: *Bone Neoplasms/drug therapy/genetics/pathology; Cell Line, Tumor; Child; Drug Resistance; Gene Expression Regulation, Neoplastic; Histone Demethylases/genetics/metabolism; Humans; Mitochondria/metabolism; Oncogene Proteins, Fusion/genetics/metabolism; Proto-Oncogene Protein c-fli-1/genetics/metabolism; RNA-Binding Protein EWS/genetics/metabolism; *Sarcoma, Ewing/drug therapy/genetics/pathology
Department(s): Laboratory Research
PubMed ID: 35298000
Publisher's Version: https://doi.org/10.1158/1541-7786.MCR-22-0027
Open Access at Publisher's Site: https://doi.org/10.1158/1541-7786.Mcr-22-0027
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-04-24 06:04:45

Last Modified: 2025-04-24 06:06:07