A Double-Negative Prostate Cancer Subtype is Vulnerable to SWI/SNF-Targeting Degrader Molecules.
Publisher DOI
PubMed ID
41534092
Abstract
Proteolysis targeting chimera (PROTAC) therapies degrading SWI/SNF ATPases interfere with androgen receptor (AR) signaling in AR-dependent castration-resistant prostate cancer (CRPC-AR). To explore the utility of SWI/SNF therapy beyond AR-sensitive CRPC, we investigated SWI/SNF-targeting agents in AR-negative CRPC. SWI/SNF targeting PROTAC treatment of cell lines and organoid models reduced the viability of not only CRPC-AR but also WNT signaling dependent AR-negative CRPC (CRPC-WNT). The CRPC-WNT subgroup represents 11% of around 400,000 cases of CRPC worldwide who die yearly of CRPC. SWI/SNF ATPase SMARCA4 depletion interfered with the master transcriptional regulator TCF7L2 in CRPC-WNT. Functionally, TCF7L2 maintained proliferation via the MAPK signaling axis in this subtype of CRPC. Together, these data provide a mechanistic rationale for interventions that perturb DNA binding of the pro-proliferative transcription factor TCF7L2 and/or direct MAPK signaling inhibition in the CRPC-WNT subclass of advanced prostate cancer.
Date Issued
2026-04-02
Publication Type
Article
Subject(s)
Language(s)
en
Author(s)
Yao, Xiaosai | |
Lillis, Nicholas | |
Shah, Sagar R | |
Leung, Alden King-Yung | |
Institute of Animal Pathology, Laboratory Cancer Therapy Escape I | |
Naveed, Alina | |
Daniel, Bence | |
Shi, Minyi | |
Tremblay, Julien | |
Cassanmagnago, Giada Andrea | |
Bolis, Marco | |
Beltran, Himisha | |
Yu, Haiyuan | |
Quigley, David A | |
Yauch, Robert L |
Additional Credits
Institute of Animal Pathology, Laboratory Cancer Therapy Escape I
Journal
Cancer Research
Publisher
American Association for Cancer Research
ISSN
1538-7445
0008-5472
Access(Rights)
embargo