Hirani Rahim, Nandakumar Subhiksha, Zaman Nabila, Prabhakaraalva Prathiksha, King Sarah Ann, Kalidindi Teja Muralidhar, Ghale Romina, Rajanala Sai Harisha, Fidele Deborah C, De Stanchina Elisa, Mary Lee Gwo-Shu, Taplin Mary Ellen, Balk Steven P, Sowalsky Adam G, Morris Michael J, Kishore Pillarsetty Naga Vara, Stopsack Konrad H, Gopalan Anuradha, Mucci Lorelei A, Kyprianou Natasha, Tewari Ashutosh K, Danila Daniel, Kantoff Philip W, Chakraborty Goutam
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.
Cell Rep. 2025 Jun 24;44(6):115779. doi: 10.1016/j.celrep.2025.115779. Epub 2025 May 30.
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.
雄激素剥夺疗法（ADT）后的疾病进展以及去势抵抗的出现是前列腺癌患者死亡的主要原因。由于目前在激素敏感型前列腺癌（CSPC）中缺乏与ADT抵抗相关的已知驱动改变，我们研究了细胞信号网络间串扰在早期去势抵抗中的关键作用。我们的临床前实验以及对临床试验RNA测序数据的分析显示，ADT后CSPC细胞中BCL2几乎普遍上调。从机制上讲，我们的研究结果突出了BCL2在协调雄激素受体（AR）-BCL2和磷脂酰肌醇3激酶（PI3K）途径之间相互信号传导中的非经典功能，特别是在ADT后，这可能促使CSPC转变为致命的去势抵抗性前列腺癌（CRPC）。至关重要的是，我们的结果提供了一个科学依据，即应在CSPC中联合ADT试验BCL2抑制，以阻止或延迟ADT诱导的CSPC向CRPC的转变，但如果在已经患有CRPC的患者中进行测试可能无效。
