A Double-Negative Prostate Cancer Subtype Is Vulnerable to SWI/SNF-Targeting Degrader Molecules

Phillip Thienger; Irene Paassen; Xiaosai Yao; Philip D. Rubin; Marika Lehner; Nicholas Lillis; Andrej Benjak; Sagar R. Shah; Alden King Yung Leung; Simone de Brot; Alina Naveed; Bence Daniel; Minyi Shi; Julien Tremblay; Joanna Triscott; Giada Andrea Cassanmagnago; Marco Bolis; Lia Mela; Himisha Beltran; Yu Chen; Salvatore Piscuoglio; Haiyuan Yu; Charlotte K.Y. Ng; David A. Quigley; Robert L. Yauch; Mark A. Rubin

doi:10.1158/0008-5472.CAN-25-2928

A Double-Negative Prostate Cancer Subtype Is Vulnerable to SWI/SNF-Targeting Degrader Molecules

Phillip Thienger
, Irene Paassen
, Xiaosai Yao
, Philip D. Rubin
, Marika Lehner
, Nicholas Lillis
, Andrej Benjak
, Sagar R. Shah
, Alden King Yung Leung
, Simone de Brot
, Alina Naveed
, Bence Daniel
, Minyi Shi
, Julien Tremblay
, Joanna Triscott
, Giada Andrea Cassanmagnago
, Marco Bolis
, Lia Mela
, Himisha Beltran
, Yu Chen

Salvatore Piscuoglio, Haiyuan Yu, Charlotte K.Y. Ng, David A. Quigley, Robert L. Yauch, Mark A. Rubin

Research output: Contribution to journal › Article › peer-review

2 Citations (Scopus)

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 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.

Original language	English
Pages (from-to)	1570-1585
Number of pages	16
Journal	Cancer Research
Volume	86
Issue number	7
DOIs	https://doi.org/10.1158/0008-5472.CAN-25-2928
Publication status	Published - 2 Apr 2026
Externally published	Yes

Keywords

Humans
Male
Gene Expression Regulation, Neoplastic/drug effects
Wnt Signaling Pathway/drug effects
Xenograft Model Antitumor Assays
DNA Helicases/metabolism
Animals
Transcription Factors/metabolism
Transcription Factor 7-Like 2 Protein/metabolism
Nuclear Proteins/metabolism
Cell Line, Tumor
Mice
Cell Proliferation/drug effects
Prostatic Neoplasms, Castration-Resistant/drug therapy
Receptors, Androgen/metabolism

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10.1158/0008-5472.CAN-25-2928

Cite this

Thienger, P., Paassen, I., Yao, X., Rubin, P. D., Lehner, M., Lillis, N., Benjak, A., Shah, S. R., Leung, A. K. Y., de Brot, S., Naveed, A., Daniel, B., Shi, M., Tremblay, J., Triscott, J., Cassanmagnago, G. A., Bolis, M., Mela, L., Beltran, H., ... Rubin, M. A. (2026). A Double-Negative Prostate Cancer Subtype Is Vulnerable to SWI/SNF-Targeting Degrader Molecules. Cancer Research, 86(7), 1570-1585. https://doi.org/10.1158/0008-5472.CAN-25-2928

@article{7313517a981542ff99a109442575932c,

title = "A Double-Negative Prostate Cancer Subtype Is Vulnerable to SWI/SNF-Targeting Degrader Molecules",

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 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.",

keywords = "Humans, Male, Gene Expression Regulation, Neoplastic/drug effects, Wnt Signaling Pathway/drug effects, Xenograft Model Antitumor Assays, DNA Helicases/metabolism, Animals, Transcription Factors/metabolism, Transcription Factor 7-Like 2 Protein/metabolism, Nuclear Proteins/metabolism, Cell Line, Tumor, Mice, Cell Proliferation/drug effects, Prostatic Neoplasms, Castration-Resistant/drug therapy, Receptors, Androgen/metabolism",

author = "Phillip Thienger and Irene Paassen and Xiaosai Yao and Rubin, \{Philip D.\} and Marika Lehner and Nicholas Lillis and Andrej Benjak and Shah, \{Sagar R.\} and Leung, \{Alden King Yung\} and \{de Brot\}, Simone and Alina Naveed and Bence Daniel and Minyi Shi and Julien Tremblay and Joanna Triscott and Cassanmagnago, \{Giada Andrea\} and Marco Bolis and Lia Mela and Himisha Beltran and Yu Chen and Salvatore Piscuoglio and Haiyuan Yu and Ng, \{Charlotte K.Y.\} and Quigley, \{David A.\} and Yauch, \{Robert L.\} and Rubin, \{Mark A.\}",

note = "{\textcopyright}2026 The Authors; Published by the American Association for Cancer Research.",

year = "2026",

month = apr,

day = "2",

doi = "10.1158/0008-5472.CAN-25-2928",

language = "English",

volume = "86",

pages = "1570--1585",

journal = "Cancer Research",

issn = "0008-5472",

publisher = "American Association for Cancer Research Inc.",

number = "7",

}

Thienger, P, Paassen, I, Yao, X, Rubin, PD, Lehner, M, Lillis, N, Benjak, A, Shah, SR, Leung, AKY, de Brot, S, Naveed, A, Daniel, B, Shi, M, Tremblay, J, Triscott, J, Cassanmagnago, GA, Bolis, M, Mela, L, Beltran, H, Chen, Y, Piscuoglio, S, Yu, H, Ng, CKY, Quigley, DA, Yauch, RL & Rubin, MA 2026, 'A Double-Negative Prostate Cancer Subtype Is Vulnerable to SWI/SNF-Targeting Degrader Molecules', Cancer Research, vol. 86, no. 7, pp. 1570-1585. https://doi.org/10.1158/0008-5472.CAN-25-2928

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.

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 -

A Double-Negative Prostate Cancer Subtype Is Vulnerable to SWI/SNF-Targeting Degrader Molecules

Abstract

Keywords

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