Dual inhibition of HSF1 and DYRK2 impedes cancer progression

Tandon, V., Moreno, R., Allmeroth, K., Quinn, J. , Wiley, S. E., Nicely, L. G., Denzel, M. S., Edwards, J. , de la Vega, L. and Banerjee, S. (2023) Dual inhibition of HSF1 and DYRK2 impedes cancer progression. Bioscience Reports, 34(1), BSR2022210. (doi: 10.1042/BSR20222102) (PMID:36622366) (PMCID:PMC9894012)

Abstract

Preserving proteostasis is a major survival mechanism for cancer. DYRK2 is a key oncogenic kinase that directly activates the transcription factor HSF1 and the 26S proteasome. Targeting DYRK2 has proven to be a tractable strategy to target cancers sensitive to proteotoxic stress, however, the development of HSF1 inhibitors remains in its infancy. Importantly, multiple other kinases have been shown to redundantly activate HSF1 which promoted ideas to directly target HSF1. The eventual development of direct HSF1 inhibitor KRIBB11 suggests that the transcription factor is indeed a druggable target. The current study establishes that concurrent targeting of HSF1 and DYRK2 can indeed impede cancer by inducing apoptosis faster than individual targetting. Furthermore, targeting the DYRK2-HSF1 axis induces death in proteasome inhibitor resistant cells and reduces triple-negative breast cancer burden in ectopic and orthotopic xenograft models. Together the data indicate that co-targeting of kinase DYRK2 and its substrate HSF1 could prove to be a beneficial strategy in perturbing neoplastic malignancies.

• Item Type: Articles
• Additional Information: This work was supported by grants from the Cancer Research UK EDDPMAMay21\100005 (to S.B.) and C52419/A22869 (to L. d. l. V.); Ninewells Cancer Campaign Cancer Research grant (to S.B.) and studentship (to V.T.); Royal Society RGS\R2\212056 (to S.B.); Tenovus Scotland T21-05 (to S.B.).
• Keywords: Stress kinases, myeloma, proteasomes, inhibition.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Quinn, Dr Jean and Edwards, Professor Joanne

Creator Roles

Quinn, J.: Resources, Data curation, Software, Validation, Investigation, Visualization, Methodology
Edwards, J.: Resources, Supervision, Funding acquisition, Formal analysis, Validation

• Authors: Tandon, V., Moreno, R., Allmeroth, K., Quinn, J., Wiley, S. E., Nicely, L. G., Denzel, M. S., Edwards, J., de la Vega, L., and Banerjee, S.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Bioscience Reports
• Publisher: Portland Press
• ISSN: 0144-8463
• ISSN (Online): 1573-4935
• Published Online: 09 January 2023
• Copyright Holders: Copyright © 2023 The Authors
• First Published: First published in Bioscience Reports 43(1): BSR2022210
• Publisher Policy: Reproduced under a Creative Commons License