Drug target proteome profiling identifies HES1-driven mitotic catastrophe in ovarian serous carcinoma - UTU Research Portal

A1 Refereed original research article in a scientific journal

Drug target proteome profiling identifies HES1-driven mitotic catastrophe in ovarian serous carcinoma

Authors: Bao, Jie; Pikkusaari, Sanna; Dai, Jun; Leppiniemi, Samuel; Huang, Wenjun; Yang, Weiming; Anil, Anu; Pääkkönen, Mirva; Lei, Chuqi; Mendoza-Ortiz, Eva Daniela; Karagöz, Ezgi; Eriksson, Johanna; Li, Min; Hynninen, Johanna; Kauko, Otto; Färkkilä, Anniina; Vähärautio, Anna; Hautaniemi, Sampsa; Kauppi, Liisa; Tang, Jing

Publisher: Elsevier

Publication year: 2025

Journal: Biomedicine and Pharmacotherapy

Article number: 118716

Volume: 193

ISSN: 0753-3322

eISSN: 1950-6007

DOI: https://doi.org/10.1016/j.biopha.2025.118716

Publication's open availability at the time of reporting: Open Access

Publication channel's open availability : Open Access publication channel

Web address : https://doi.org/10.1016/j.biopha.2025.118716

Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/505281223

Abstract

Ovarian high-grade serous cancer (HGSC) is the most aggressive ovarian cancer subtype with limited treatment options. We identify the PDPK1 inhibitor BX-912 as a promising candidate, showing strong single-agent activity and synergy with the PARP inhibitor olaparib, independent of BRCA status. Unexpectedly, BX-912 induces multinucleation, a phenotype not seen with other PDPK1 inhibitors. Proteome Integral Solubility Alteration (PISA) assay reveals HES1 as a functional off-target, while structural modeling suggested BX-912 acts as a protein–protein interaction modulator, driving nuclear accumulation of HES1 complexes and hence inducing mitotic catastrophe. Cell-cycle analyses confirm enhanced DNA damage response and G2/M arrest when combined with olaparib. These findings uncover a novel mechanism for BX-912, establish HES1 inhibition as a therapeutic strategy in HGSC, demonstrate proteomics’ power to reveal hidden drug activities, and propose sequential cell-cycle targeting to improve treatment efficacy.

Downloadable publication

This is an electronic reprint of the original article.
This reprint may differ from the original in pagination and typographic detail. Please cite the original version.

1-s2.0-S0753332225009102-main.pdf

Funding information in the publication:
SL: The iCANDOC Precision Cancer Medicine pilot
SH: European Union’s Horizon 2020 Research and Innovation Programme under grant agreements 965193 (DECIDER), the Sigrid Jusélius Foundation and Cancer Foundation Finland.
LK: the Sigrid Jusélius Foundation and Cancer Foundation Finland
WY: The EDUFI Fellowship from the Finnish National Agency for Education
JB and JT: European Research Council (DrugComb No. 716063), The Sigrid Jusélius Foundation, The Academy of Finland (No. 317680, 320131, 359752)