Characterizing resistance in prostate cancer at a single cell level with hormonal treatment and epigenetic inhibitors

Late-stage prostate cancer is treated with hormonal therapy. While initially effective, development of drug resistance is common. Hypoxia, a local-environmental occurrence in tumours, is known to trigger hormone-independence and concurrent drug resistance in cancer cells.

Here we analyse single-cell transcriptomes of LNCaP cells throughout drug treatment. These cells were exposed to chronic hypoxia and treated with Enzalutamide, a hormonal drug which inhibits the androgen receptor, both with and without Tazemetostat, an epigenetic drug that inhibits EZH2 catalytic activity, which renders Enzalutamide-resistant clones partially sensitive to hormonal therapies. We identify genes characterizing the resistant clone and assess clinical relevance.

We characterize a resistant cluster present with Enzalutamide treatment but not with combination therapy. The top 10 upregulated genes in this cluster included genes previously linked to resistance: DDIT3, MDM2, and CDKN1A, and one previously proposed as a pan-cancer hallmark (HSP90B1). Analysis of clinical databases showed expression of CDKN1A, POLH, and GADD54 to be significantly upregulated in association with neuroendocrine prostate cancer.

This work characterizes at a single-cell level the Enzalutamide resistant clone and the impact of epigenetic inhibitors on resistance development. This characterization may enable the identification of resistant and non-resistant cells by their gene expression profile.