Integrative molecular analyses define correlates of high B7-H3 expression in metastatic castrate-resistant prostate cancer.
Xiaolei ShiAbderrahman DayHannah E BergomSydney TapeSylvan C BacaZoi E SychevGabrianne LarsonAsha BozicevichJustin M DrakeNicholas A ZorkoJinhua WangCharles J RyanEmmanuel S AntonarakisJustin H HwangPublished in: NPJ precision oncology (2022)
B7-H3 (CD276) is an immune checkpoint overexpressed in prostate cancer with minimal expression in normal tissues and associated with poor prognosis, making it an excellent therapy target. We interrogated B7-H3 expression and its regulation in metastatic castration-resistant prostate cancer (mCRPC). We found greater expression of B7-H3 transcript relative to other immunotherapy targets (CTLA-4, PD-L1/2), including in tumors that lacked expression of prostate-specific membrane antigen (PSMA). Enzalutamide-resistant mCRPC cells demonstrated increased amounts of B7-H3, and this was associated with resistance signaling pathways. Using a machine-learning algorithm, the gene network of B7-H3 was strongly correlated with androgen receptor (AR) and AR co-factor (HOXB13, FOXA1) networks. In mCRPC samples, the B7-H3 promoter and distal enhancer regions exhibited enhanced transcriptional activity and were directly bound by AR and its co-factors. Altogether, our study characterizes molecular profiles and epigenetic regulation of B7-H3-expressing mCRPC tumors, which informs optimal precision-oncology approaches for mCRPC patients.
Keyphrases
- poor prognosis
- prostate cancer
- long non coding rna
- machine learning
- gene expression
- small cell lung cancer
- squamous cell carcinoma
- binding protein
- radical prostatectomy
- induced apoptosis
- ejection fraction
- computed tomography
- mesenchymal stem cells
- newly diagnosed
- prognostic factors
- chronic kidney disease
- minimally invasive
- copy number
- endoplasmic reticulum stress
- genome wide
- pi k akt
- cell death
- rna seq
- heat shock
- peritoneal dialysis
- single cell
- heat stress