G protein signaling of oxytocin receptor as a potential target for cabazitaxel-resistant prostate cancer

Abstract

Although the treatment armamentarium for patients with metastatic prostate cancer has improved recently, treatment options after progression on cabazitaxel (CBZ) are limited. To identify the mechanisms underlying CBZ resistance and new therapeutic targets, we performed single-cell RNA sequencing of circulating tumor cells (CTCs) from patients with CBZ-resistant prostate cancer. Cells were clustered based on gene expression profiles. In silico screening was used to nominate candidate drugs for overcoming CBZ resistance in castration-resistant prostate cancer. CTCs were divided into 3–4 clusters, reflecting intra-patient tumor heterogeneity in refractory prostate cancer. Pathway analysis revealed that clusters in two cases showed upregulation of the oxytocin (OXT) receptor signaling pathway. Spatial gene expression analysis of CBZ-resistant prostate cancer tissues confirmed the heterogeneous expression of OXT signaling molecules. Cloperastine had significant antitumor activity against CBZ-resistant prostate cancer cells. Mass spectrometric phosphoproteome analysis revealed the suppression of OXT signaling specific to CBZ-resistant models. These results support the potential of cloperastine as a candidate drug for overcoming CBZ-resistant prostate cancer via the inhibition of OXT signaling.