Cell reports · 2025
BCL2 drives castration resistance in castration-sensitive prostate cancer by orchestrating reciprocal crosstalk between oncogenic pathways.
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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
Аннотация
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.