PhD Scientific Days 2023

Molecular Sciences - Posters L

In Silico and In Vitro Investigation of NAMPT in the Chemotherapy Resistance of Prostate Cancer

Text of the abstract

Introduction:
Docetaxel (DOC) is a frequently used first-line chemotherapy in metastatic castration-resistant prostate cancer (mCRPC). Baseline or acquired resistance often occurs, but the contributing mechanisms are still not fully understood. High-throughput omics techniques provide proper datasets for network analysis aiming for a broader perspective.

Aims:
Our aim is to identify proteins involved in DOC-resistance in order to find new drug targets and therapy-predictive serum markers.

Methods:
PC3 and DU145 prostate cancer cell lines and their DOC-resistant (DR) subclones (PC3-DR; DU145-DR) were comparatively analyzed by RNA-Seq. Results were processed using bioinformatics and network science tools in order to find candidates. An outstanding DOC-resistance related protein, NAMPT was measured in serum samples of DOC-treated mCRPC patients by ELISA and the concentrations were correlated with clinicopathological and survival data. We have also characterized the role of NAMPT in large signaling network databases (OmniPath, SIGNOR, Reactome FI) to explore its role and druggability in DOC-resistance.

Result:
Cross-reference analysis with data sets of independent studies identified NAMPT consequently upregulated in DR cells. Elevated pretreatment NAMPT serum levels correlated with poor patients’ survival (p=0.012). The multivariate model revealed higher pretreatment NAMPT serum levels as independent predictors of poor survival in DOC-treated mCRPC patients. Furthermore, NAMPT serum levels were significantly higher before and at radiographic disease progression compared to baseline values. We have found that NAMPT is a source node in the OmniPath network which suggests its large influence on its neighborhood. Moreover, the neighbors of NAMPT are associated with various areas such as epithelial-mesenchymal transition, growth factor and cytokine signaling and metabolism.

Conclusion:
Our results imply that serum NAMPT level might be used as a biomarker for the identification of DOC-resistant patients and may therefore help to optimize future clinical decision-making. Inhibiting a source node like NAMPT could have diverse effects on cellular functions. Therefore, further experimentation is needed to assess the functional involvement of NAMPT in the resistance mechanism.

Funding:
ÚNKP-22-4-I-SE-25; OTKA K131458; TKP2021-EGA-24