Synapse - BCL2 drives castration resistance in castration-sensitive prostate cancer by orchestrating reciprocal crosstalk between oncogenic pathways

BCL2 drives castration resistance in castration-sensitive prostate cancer by orchestrating reciprocal crosstalk between oncogenic pathways Journal Article

Authors:	Hirani, R.; Nandakumar, S.; Zaman, N.; Prabhakaraalva, P.; King, S. A.; Kalidindi, T. M.; Ghale, R.; Rajanala, S. H.; Fidele, D. C.; De Stanchina, E.; Mary Lee, G. S.; Taplin, M. E.; Balk, S. P.; Sowalsky, A. G.; Morris, M. J.; Kishore Pillarsetty, N. V.; Stopsack, K. H.; Gopalan, A.; Mucci, L. A.; Kyprianou, N.; Tewari, A. K.; Danila, D.; Kantoff, P. W.; Chakraborty, G.
Article Title:	BCL2 drives castration resistance in castration-sensitive prostate cancer by orchestrating reciprocal crosstalk between oncogenic pathways
Abstract:	Progression following androgen-deprivation therapy (ADT) and the development of castration resistance is the leading cause of death among prostate cancer patients. Since there is currently a lack of known driver alterations associated with ADT resistance in castration-sensitive prostate cancer (CSPC), we investigated the critical role of crosstalk between cell signaling networks in early castration resistance. Our preclinical experiments and analyses of RNA sequencing data from clinical trials revealed nearly universal upregulation of BCL2 after ADT in CSPC cells. Mechanistically, our findings highlight a non-canonical function of BCL2 in orchestrating reciprocal signaling between the androgen receptor (AR)-BCL2 and phosphatidylinositol 3-kinase (PI3K) pathways, particularly upon ADT, potentially driving CSPC transformation into lethal castration-resistant prostate cancer (CRPC). Critically, our results provide a scientific rational that BCL2 inhibition should be trialed in CSPC in combination with ADT to impede or delay ADT-induced CSPC-to-CRPC transformation but may be ineffective if tested in patients who already have CRPC. © 2025 The Authors
Keywords:	immunohistochemistry; signal transduction; controlled study; protein expression; gene mutation; human cell; drug potentiation; nonhuman; flow cytometry; mouse; cell viability; cell survival; protein bcl 2; reverse transcription polymerase chain reaction; apoptosis; signaling; animal experiment; animal model; small interfering rna; caspase 3; immunofluorescence; protein p53; uvomorulin; prostate cancer; genetic transfection; western blotting; androgen receptor; real time polymerase chain reaction; combination therapy; androgen deprivation therapy; beta catenin; castration resistant prostate cancer; tumor microenvironment; hedgehog; ar; growth curve; enzalutamide; cellular plasticity; human; article; rna sequencing; cell growth assay; differential expression analysis; lncap cell line; venetoclax; adt; cp: cancer; bcl 2; pi3 kinase signaling
Journal Title:	Cell Reports
Volume:	44
Issue:	6
ISSN:	2211-1247
Publisher:	Cell Press
Date Published:	2025-06-24
Start Page:	115779
Language:	English
DOI:	10.1016/j.celrep.2025.115779
PROVIDER:	scopus
PUBMED:	40448998
PMCID:	PMC12316453
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-105006534023&doi=10.1016%2fj.celrep.2025.115779&partnerID=40&md5=885eaf365d1d9eaefe50e58021212acc
Notes:	The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Source: Scopus