Dual downregulation of HRK and BAD promotes BCL-xL-mediated docetaxel resistance in prostate cancer

Year: 2026

Type: article

Abstract: Prostate cancer is the second most common malignancy in men. For patients who present metastatic disease, androgen deprivation therapy is the standard of care. Despite significant initial responses to anti-androgenic therapy, almost all patients progress to an incurable metastatic castration-resistant prostate cancer, facing a significant therapeutic challenge. Docetaxel is a taxane that improves response rates in these patients, but its efficacy is limited due to the development of resistance, which can be mediated through anti-apoptotic adaptations. Dynamic BH3 profiling is a functional assay that can anticipate tumors’ anti-apoptotic adaptation to treatment and guide the use of specific inhibitors such as BH3 mimetics or PROTACs. In this study, we elucidate that BCL-xL is the major pro-survival protein in prostate cancer cell lines after docetaxel treatment, which can be reverted using BH3 mimetics or PROTAC strategies against this protein. We also describe for the first time that the downregulation of HRK and BAD sensitizer BH3-only proteins due to docetaxel treatment leads to BCL-xL mediated resistance in prostate cancer cells. Finally, we introduce a new functional technology that detects mitochondrial permeabilization, enabling successful testing of this therapeutic combination directly in patient‑derived prostate cancer cells.

Source: Oncogenesis

DOI: 10.1038/s41389-026-00652-y

Authors: Clara Alcon, Albert Manzano-Muñoz, Vicenç Ruiz de Porras, Pol Servian, Arnau Abella-Serra, Maria Fernandez-Saorin, Albert Lu, Josep Samitier, Albert Font, Joan Montero

Institutions: Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Universitat de Barcelona, Universitat Pompeu Fabra, Hospital Universitari Germans Trias i Pujol, Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine, Barcelona Institute of Science and Technology, Institute for Bioengineering of Catalonia, Institut Català d'Oncologia

Language: English

Topic: Cell death mechanisms and regulation

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $4,290

Funders: Fundación Cellex, Ministerio de Ciencia, Innovación y Universidades, Centres de Recerca de Catalunya, Generalitat de Catalunya, Institució Catalana de Recerca i Estudis Avançats, José Carreras Leukämie-Stiftung, Universitat de Barcelona, Institute for Bioengineering of Catalonia, National Institutes of Health, Agència de Gestió d'Ajuts Universitaris i de Recerca, Instituto de Salud Carlos III, European Regional Development Fund, Agencia Estatal de Investigación

OpenAlex ID: W7203792976