Abstract
Emergence of an aggressive androgen receptor (AR)-independent neuroendocrine prostate cancer (NEPC) after androgen-deprivation therapy (ADT) is well-known. Nevertheless, the majority of advanced-stage prostate cancer patients, including those with SPINK1-positive subtype, are treated with AR-antagonists. Here, we show AR and its corepressor, REST, function as transcriptional-repressors of SPINK1, and AR-antagonists alleviate this repression leading to SPINK1 upregulation. Increased SOX2 expression during NE-transdifferentiation transactivates SPINK1, a critical-player for maintenance of NE-phenotype. SPINK1 elicits epithelial-mesenchymal-transition, stemness and cellular-plasticity. Conversely, pharmacological Casein Kinase-1 inhibition stabilizes REST, which in cooperation with AR causes SPINK1 transcriptional-repression and impedes SPINK1-mediated oncogenesis. Elevated levels of SPINK1 and NEPC markers are observed in the tumors of AR-antagonists treated mice, and in a subset of NEPC patients, implicating a plausible role of SPINK1 in treatment-related NEPC. Collectively, our findings provide an explanation for the paradoxical clinical-outcomes after ADT, possibly due to SPINK1 upregulation, and offers a strategy for adjuvant therapies.
Highlights
Emergence of an aggressive androgen receptor (AR)-independent neuroendocrine prostate cancer (NEPC) after androgen-deprivation therapy (ADT) is well-known
We conjecture that SPINK1 is one of the AR repressed genes, we examined the expression of AR and other members of AR repressor complex (NCOR1, NCOR2, and NRIP1) using TCGA-prostate adenocarcinoma (PRAD) cohort, and the patients were sorted based on SPINK1 high and low expression by employing quartile-based normalization[34]
Our findings show an inverse association between SPINK1 expression and AR signaling in prostate cancer (PCa) patients, indicating that upregulation of SPINK1 is owing to the loss of AR-mediated repression during PCa progression
Summary
Emergence of an aggressive androgen receptor (AR)-independent neuroendocrine prostate cancer (NEPC) after androgen-deprivation therapy (ADT) is well-known. Androgen deprivation therapy (ADT) remains the goldstandard for treating advanced PCa, the disease often progresses as castrate-resistant prostate cancer (CRPC), associated with poor prognosis[16,17]. Current treatment regimen for CRPC patients include enzalutamide (MDV3100) and apalutamide (ARN-509) (which blocks AR nuclear translocation and its genomic binding), and abiraterone acetate (an irreversible steroidal CYP17A1 inhibitor, that targets adrenal and intratumoral androgen biosynthesis)[21,22,23] These AR-targeted therapies are known to prolong the overall survival of patients, the response is temporary, and the disease eventually progresses. Our findings draw attention towards the widespread use of AR antagonists and the plausible emergence of a distinct resistance mechanism associated with ADT-induced SPINK1 upregulation in prostate cancer
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