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.
Cell reports. 2025 May 30 [Epub ahead of print]
Rahim Hirani, Subhiksha Nandakumar, Nabila Zaman, Prathiksha Prabhakaraalva, Sarah Ann King, Teja Muralidhar Kalidindi, Romina Ghale, Sai Harisha Rajanala, Deborah C Fidele, Elisa De Stanchina, Gwo-Shu Mary Lee, Mary Ellen Taplin, Steven P Balk, Adam G Sowalsky, Michael J Morris, Naga Vara Kishore Pillarsetty, Konrad H Stopsack, Anuradha Gopalan, Lorelei A Mucci, Natasha Kyprianou, Ashutosh K Tewari, Daniel Danila, Philip W Kantoff, Goutam Chakraborty
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Departments of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Departments of Oncological Sciences Icahn School of Medicine at Mount Sinai, New York, NY, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Department of Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA., Genitourinary Malignancies Branch, National Cancer Institute, NIH, Bethesda, MD, USA., Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA., Departments of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Convergent Therapeutics Inc., Boston, MA, USA., Departments of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Departments of Oncological Sciences Icahn School of Medicine at Mount Sinai, New York, NY, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: .
PubMed http://www.ncbi.nlm.nih.gov/pubmed/40448998