{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:17:15Z","timestamp":1785403035807,"version":"3.56.0"},"posted":{"date-parts":[[2024,3,27]]},"group-title":"Cancer Biology","reference-count":81,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,3,27]],"date-time":"2024-03-27T00:00:00Z","timestamp":1711497600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Prostate Cancer Fondation"},{"name":"Benioff Initiative for Prostate Cancer Research"},{"award":["SPORE 1P50CA275741"],"award-info":[{"award-number":["SPORE 1P50CA275741"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"Department of Defense","doi-asserted-by":"crossref","award":["W81XWH-22-1-0833"],"award-info":[{"award-number":["W81XWH-22-1-0833"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000005","name":"Department of Defense","doi-asserted-by":"crossref","award":["HT94252410252"],"award-info":[{"award-number":["HT94252410252"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000005","name":"Department of Defense","doi-asserted-by":"crossref","award":["HT94252410123"],"award-info":[{"award-number":["HT94252410123"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,9,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Proteolysis targeting chimera (PROTAC) therapies degrading SWI\/SNF ATPases offer a novel approach to 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. We discovered that SWI\/SNF ATPase SMARCA4 depletion interfered with the master transcriptional regulator TCF7L2 (TCF4) in CRPC-WNT. Functionally, TCF7L2 maintains proliferation via the MAPK signaling axis in this subtype of CRPC. These data suggest a mechanistic rationale for interventions that perturb the DNA binding of the pro-proliferative TCF7L2 transcription factor (TF) and\/or direct MAPK signaling inhibition in the CRPC-WNT subclass of advanced prostate cancer.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Statement of significance<\/jats:title>\n                  <jats:p>Androgen receptor (AR)-negative prostate cancer (PCa) remains a clinical challenge due to the lack of targeted therapeutic options. Here, we identified a lineage-defining molecular axis in a subtype of AR- negative PCa, accounting for around 10% of castration-resistant PCa (CRPC) that can be interfered with by SWI\/SNF-targeting agents.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.03.24.586276","type":"posted-content","created":{"date-parts":[[2024,3,27]],"date-time":"2024-03-27T15:01:00Z","timestamp":1711551660000},"source":"Crossref","is-referenced-by-count":3,"title":["A double-negative prostate cancer subtype is vulnerable to SWI\/SNF-targeting degrader molecules"],"prefix":"10.64898","author":[{"given":"Phillip","family":"Thienger","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-7737-3292","authenticated-orcid":false,"given":"Irene","family":"Paassen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaosai","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip D.","family":"Rubin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marika","family":"Lehner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Lillis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4522-6575","authenticated-orcid":false,"given":"Andrej","family":"Benjak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sagar R.","family":"Shah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alden King-Yung","family":"Leung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3049-0103","authenticated-orcid":false,"given":"Simone","family":"de Brot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alina","family":"Naveed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bence","family":"Daniel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minyi","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julien","family":"Tremblay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna","family":"Triscott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giada Andrea","family":"Cassanmagnago","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Bolis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lia","family":"Mela","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Himisha","family":"Beltran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2686-2939","authenticated-orcid":false,"given":"Salvatore","family":"Piscuoglio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyuan","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6100-0026","authenticated-orcid":false,"given":"Charlotte K Y","family":"Ng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Quigley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9478-6283","authenticated-orcid":false,"given":"Robert L.","family":"Yauch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark A.","family":"Rubin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025090617100663000_2024.03.24.586276v2.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2017.09.003"},{"key":"2025090617100663000_2024.03.24.586276v2.2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abn0478"},{"key":"2025090617100663000_2024.03.24.586276v2.3","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4045"},{"key":"2025090617100663000_2024.03.24.586276v2.4","doi-asserted-by":"crossref","unstructured":"Ye, Y. , Chen, X. & Zhang, W . 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