Transcriptomic Analysis of Patients with Metastatic Hormone-Sensitive Prostate Cancer to Identify Genomic Signatures Involved in the Transition from Androgen-Dependent to Androgen-Independent Phenotype
Pecoraro 1, D. Esposito 1, F. Di Costanzo 1, F. Migliaccio 1, C. Barraco 1, V. Conteduca 2, S. Rossetti 3, S. Scagliarini 4, R. Bianco 1, L. Formisano 1
(1) University of Naples “Federico II” – Italy, (2) University of Foggia – Italy, (3) Istituto Nazionale Tumori “Fondazione Pascale” – Italy, (4) AORN Antonio Cardarelli – Italy
Objective:
The study aims to identify genomic signatures characterizing the transition from androgen-dependent to androgen-independent phenotypes in metastatic hormone-sensitive prostate cancer (mHSPC) patients through comprehensive gene expression analysis of those undergoing doublet therapy (ADT + ARPI).
Methods:
Patients with mHSPC treated with ADT plus ARPI was selected for transcriptomic profiling. Total RNA was extracted from Formalin-Fixed Paraffin-Embedded (FFPE) tissue samples using the Maxwell® RSC RNA FFPE Kit. The NanoString Tumor Signaling 360 Panel was employed to profile 780 human genes involved in tumor signaling. Bioinformatics tools were used to identify differentially expressed genes (DEGs), deregulated pathways, and potential regulatory networks. Key findings will be validated in independent patient cohorts to ensure the robustness and generalizability of the signatures.
Results:
A comprehensive transcriptomic analysis was conducted on samples from 24 mHSPC patients treated with doublet therapy (ADT+ARPI). The study focused on identifying differentially expressed genes (DEGs) between non-responder (NR) and responder (R) patients. These genes were significantly involved in various pathways that contribute to therapeutic resistance. At the stromal level, NR patients exhibited a marked increase in ligands known to activate metastasis-promoting receptors. These receptors play a crucial role in the tumor microenvironment by facilitating cancer cell migration, invasion, and ultimately metastasis. Genes involved in cell-cycle progression were also up-regulated in NR patients, promoting unchecked cellular proliferation. Additionally, there was a notable up-regulation of genes associated with androgen receptor (AR) signaling, a key driver of prostate cancer growth and progression. The concurrent increase in metastasis-promoting ligands and the dysregulation of cell-cycle progression suggest a multifaceted mechanism of resistance to hormonal therapy in NR patients. This suggests that combining hormonal therapy with chemotherapy, which can target rapidly dividing cells, could potentially overcome this resistance and improve treatment efficacy.
Conclusions:
The study identified key genomic signatures and pathways involved in the transition from androgen-dependent to androgen-independent mHSPC. These findings provide insights into the molecular mechanisms driving resistance to androgen receptor-targeted therapies and highlight potential biomarkers for early detection of therapy resistance. The identified signatures may serve as therapeutic targets for developing novel treatment strategies aimed at delaying or preventing the onset of castration resistance in prostate cancer patients.