BCL2 drives castration resistance in castration-sensitive prostate cancer by orchestrating reciprocal crosstalk between oncogenic pathways
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.
Authors
- Rahim Hirani (ORCID: https://orcid.org/0000-0002-9304-9916)
- Elisa de Stanchina (ORCID: https://orcid.org/0000-0002-3873-315X)
- Anuradha Gopalan (ORCID: https://orcid.org/0009-0007-6017-0991)
- Nagavarakishore Pillarsetty (ORCID: https://orcid.org/0000-0002-1750-7436)
- Natasha Kyprianou (ORCID: https://orcid.org/0000-0002-8713-3599)
- Goutam Chakraborty (ORCID: https://orcid.org/0000-0002-4387-2621)
- Teja Kalidindi (ORCID: https://orcid.org/0000-0002-0210-0270)
- Daniel C. Danila (ORCID: https://orcid.org/0000-0002-7647-0741)
- Gwo‐Shu Mary Lee (ORCID: https://orcid.org/0000-0001-9236-9195)
- Adam G. Sowalsky (ORCID: https://orcid.org/0000-0003-2760-1853)
- Romina Ghale
- Lorelei Ann Mucci (ORCID: https://orcid.org/0000-0002-2551-4927)
- Konrad Hermann Stopsack (ORCID: https://orcid.org/0000-0002-0722-1311)
- Philip W. Kantoff (ORCID: https://orcid.org/0000-0001-7275-0597)
- Sarah Ann King
- Ashutosh Tewari (ORCID: https://orcid.org/0000-0002-3146-4524)
- Subhiksha Nandakumar (ORCID: https://orcid.org/0000-0003-0258-3484)
- Deborah Fidele
- Sai Harisha Rajanala (ORCID: https://orcid.org/0000-0002-2117-120X)
- Michael J. Morris (ORCID: https://orcid.org/0000-0001-8802-9147)
- Steven P. Balk (ORCID: https://orcid.org/0000-0002-4546-7371)
- Nabila Zaman
- Mary Ellen Taplin
- Prathiksha Prabhakaraalva
Institutions
- Beth Israel Deaconess Medical Center (US)
- Memorial Sloan Kettering Cancer Center (US)
- Harvard University (US)
- Dana-Farber Cancer Institute (US)
- National Cancer Institute (US)
- Molecular Oncology (United States) (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-05-30
- DOI
- https://doi.org/10.1016/j.celrep.2025.115779
- Citations
- 2
- Primary Topic
- Prostate Cancer Treatment and Research
- Type
- article
- Field-Weighted Citation Impact
- 3.04