Background:

Despite advancements in therapeutic approaches, including taxane-based chemotherapy and androgen receptor targeting agents, metastatic castration-resistant prostate cancer (mCRPC) remains an incurable tumour, underlying the need of novel strategies that can target the complexities of this disease and bypass the development of drug-resistance mechanisms. We previously demonstrated the synergistic antitumor interaction of the antiepileptic with histone deacetylase inhibitory activity valproic acid (VPA), and the lipid-lowering drug simvastatin (SIM). This combination sensitizes mCRPC cells to docetaxel treatment, both in vitro and in vivo models, by targeting cancer stem cells compartment via mevalonate pathway/YAP axis modulation.

Methods:

Here, by a combined proteomic and metabolomic/lipidomic approach we characterized tumor samples derived from 22Rv1 mCRPC cells xenografted mice, treated or not with VPA/SIM combination, coupled with an in deep bioinformatics analysis.

Results:

We confirmed a specific impact of VPA/SIM on Hippo-YAP signaling pathway, functionally related with modulation of cancer-related extracellular matrix biology and metabolic reprogramming, providing further insights into the molecular mechanism of the VPA/SIM antitumor effect.

Conclusions:

In the current study, we present an in-depth exploration of the potential to repurpose in mCRPC treatment two generic and safe drugs, valproic acid (VPA) and simvastatin (SIM), that already showcased anti-tumor efficacy in combination, primarily affecting cancer stem cell compartment via MVP/YAP axis modulation. Bioinformatics analysis of LC-MS/MS proteomics and of 1H-NMR metabolomics/lipidomics results, confirmed a specific impact of VPA/SIM on Hippo-YAP