TY - JOUR
T1 - A Double-Negative Prostate Cancer Subtype Is Vulnerable to SWI/SNF-Targeting Degrader Molecules
AU - Thienger, Phillip
AU - Paassen, Irene
AU - Yao, Xiaosai
AU - Rubin, Philip D.
AU - Lehner, Marika
AU - Lillis, Nicholas
AU - Benjak, Andrej
AU - Shah, Sagar R.
AU - Leung, Alden King Yung
AU - de Brot, Simone
AU - Naveed, Alina
AU - Daniel, Bence
AU - Shi, Minyi
AU - Tremblay, Julien
AU - Triscott, Joanna
AU - Cassanmagnago, Giada Andrea
AU - Bolis, Marco
AU - Mela, Lia
AU - Beltran, Himisha
AU - Chen, Yu
AU - Piscuoglio, Salvatore
AU - Yu, Haiyuan
AU - Ng, Charlotte K.Y.
AU - Quigley, David A.
AU - Yauch, Robert L.
AU - Rubin, Mark A.
N1 - ©2026 The Authors; Published by the American Association for Cancer Research.
PY - 2026/4/2
Y1 - 2026/4/2
N2 - 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 that die yearly. 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 proproliferative transcription factor TCF7L2 and/or direct MAPK signaling inhibition in the CRPC-WNT subclass of advanced prostate cancer. SIGNIFICANCE: SWI/SNF-targeting agents interfere with a lineage-defining molecular axis in the WNT signaling-dependent, androgen receptor-negative subtype of prostate cancer, which accounts for around 10% of castration-resistant tumors.
AB - 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 that die yearly. 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 proproliferative transcription factor TCF7L2 and/or direct MAPK signaling inhibition in the CRPC-WNT subclass of advanced prostate cancer. SIGNIFICANCE: SWI/SNF-targeting agents interfere with a lineage-defining molecular axis in the WNT signaling-dependent, androgen receptor-negative subtype of prostate cancer, which accounts for around 10% of castration-resistant tumors.
KW - Humans
KW - Male
KW - Gene Expression Regulation, Neoplastic/drug effects
KW - Wnt Signaling Pathway/drug effects
KW - Xenograft Model Antitumor Assays
KW - DNA Helicases/metabolism
KW - Animals
KW - Transcription Factors/metabolism
KW - Transcription Factor 7-Like 2 Protein/metabolism
KW - Nuclear Proteins/metabolism
KW - Cell Line, Tumor
KW - Mice
KW - Cell Proliferation/drug effects
KW - Prostatic Neoplasms, Castration-Resistant/drug therapy
KW - Receptors, Androgen/metabolism
UR - https://www.scopus.com/pages/publications/105034932642
UR - https://www.mendeley.com/catalogue/156c2c01-590b-30fd-b947-80b2a489a421/
U2 - 10.1158/0008-5472.CAN-25-2928
DO - 10.1158/0008-5472.CAN-25-2928
M3 - Article
C2 - 41534092
AN - SCOPUS:105034932642
SN - 0008-5472
VL - 86
SP - 1570
EP - 1585
JO - Cancer Research
JF - Cancer Research
IS - 7
ER -