IRAK1 is a critical mediator of low molecular weight hyaluronic acid-induced stemness in high-grade serous ovarian cancer

Standing, D.; Dandawate, P.; Gunewardena, S.; Covarrubias-Zambrano, O.; Roby, K. F.; Khabele, D.; Jewell, A.; Tawfik, O.; Bossmann, S. H.; Godwin, A. K.; Weir, S. J.; Jensen, R. A.; Anant, S.

doi:10.1101/2023.09.25.559366

bioRxiv · 10.1101/2023.09.25.559366

IRAK1 is a critical mediator of low molecular weight hyaluronic acid-induced stemness in high-grade serous ovarian cancer

Standing, D.·Dandawate, P.·Gunewardena, S.·Covarrubias-Zambrano, O.·Roby, K. F.·Khabele, D.·Jewell, A.·Tawfik, O.·Bossmann, S. H.·Godwin, A. K.·Weir, S. J.·Jensen, R. A.·Anant, S.

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Abstract

Advanced epithelial ovarian cancer (EOC) survival rates are dishearteningly low, with [~]25% surviving beyond 5 years. Evidence suggests that cancer stem cells (CSCs) contribute to acquired chemoresistance and tumor recurrence. Here, we show that IRAK1 is upregulated in EOC tissues, and enhanced expression correlates with poorer overall survival. IRAK1 and BRCA1/2 mutation status are mutually exclusive. Moreover, low molecular weight hyaluronic acid (LMW HA), which is abundant in malignant ascites from patients with advanced EOC, induced IRAK1 phosphorylation leading to STAT3 activation and enhanced spheroid formation. Knockdown of IRAK1 impaired tumor growth in peritoneal disease models, and impaired HA-induced spheroid growth and STAT3 phosphorylation. Finally, we determined that TCS2210, a known inducer of neuronal differentiation in mesenchymal stem cells, is a selective inhibitor of IRAK1. TCS2210 significantly inhibited EOC growth in vitro and in vivo both as monotherapy, and in combination with cisplatin. Collectively, these data demonstrate IRAK1 as a druggable target for EOC.

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Standing, D., Dandawate, P., Gunewardena, S., Covarrubias-Zambrano, O., Roby, K. F., Khabele, D., Jewell, A., Tawfik, O., Bossmann, S. H., Godwin, A. K., Weir, S. J., Jensen, R. A., Anant, S.. 2023-09-26. IRAK1 is a critical mediator of low molecular weight hyaluronic acid-induced stemness in high-grade serous ovarian cancer. https://doi.org/10.1101/2023.09.25.559366

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