Dual inhibition of HSF1 and DYRK2 impedes cancer progression

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.

Functional Roles of DYRK2 as a Tumor Regulator

“…In addition, the overlapping expression of DYRK2 and HSF1 was observed across all cancers in TCGA database [44]. High protein expression levels of DYRK2 in the nucleus result in local and distal recurrence in patients with TNBC [44]. Moreover, distal recurrence in patients with quadruple-negative breast cancer was shorter than that in patients with low protein expression levels of DYRK2 [44].…”

“…Based on single-cell RNA sequencing datasets, a clear overlap between DYRK2 and HSF1 was detected in the clustered cell populations of renal cell carcinoma, colon adenocarcinoma, breast cancer, and astrocytoma [44]. In addition, the overlapping expression of DYRK2 and HSF1 was observed across all cancers in TCGA database [44]. High protein expression levels of DYRK2 in the nucleus result in local and distal recurrence in patients with TNBC [44].…”