Mar 20, 2020

Transcriptional mediators of treatment resistance in lethal prostate cancer

bioRxiv
Meng Xiao HeEliezer M. Van Allen

Abstract

Metastatic castration resistant prostate cancer (mCRPC) is primarily treated with therapies that prevent transcriptional activity of the androgen receptor (AR), cause DNA damage, or prevent cell division. Clinical resistance to these therapies, including second-generation androgen-targeting compounds such as enzalutamide and abiraterone, is nearly universal. Other treatment modalities, including immune checkpoint inhibitors, have provided minimal benefit except in rare subsets of patients. Both tumour intrinsic and extrinsic cellular programs contributing to therapeutic resistance remain areas of active investigation. Here we use full-length single-cell RNA-sequencing (scRNA-seq) to identify the transcriptional states of cancer and immune cells in the mCRPC microenvironment. Within cancer cells, we identified transcriptional patterns that mediate a significant proportion of inherited risk for prostate cancer, extensive heterogeneity in AR splicing within and between tumours, and vastly divergent regulatory programs between adenocarcinoma and small cell carcinoma. Moreover, upregulation of TGF-β signalling and epithelial-mesenchymal transition (EMT) were both associated with resistance to enzalutamide. We found that some lymph n...Continue Reading

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Mentioned in this Paper

Lethal
Immune Effector Cell
Up-Regulation (Physiology)
Clonal Expansion
Pharmacologic Substance
RNA Splicing
DNA Damage
Prostatic Cancer, Castration-Resistant
Transforming Growth Factor beta
Carcinoma, Small Cell

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