Transcriptional mediators of treatment resistance in lethal prostate cancer.
Metastatic castration-resistant prostate cancer is typically lethal, exhibiting intrinsic or acquired resistance to second-generation androgen-targeting therapies and minimal response to immune checkpoint inhibitors. Cellular programs driving resistance in both cancer and immune cells remain poorly understood. We present single-cell transcriptomes from 14 patients with advanced prostate cancer, spanning all common metastatic sites. Irrespective of treatment exposure, adenocarcinoma cells pervasively coexpressed multiple androgen receptor isoforms, including truncated isoforms hypothesized to mediate resistance to androgen-targeting therapies. Resistance to enzalutamide was associated with cancer cell-intrinsic epithelial-mesenchymal transition and transforming growth factor-β signaling. Small cell carcinoma cells exhibited divergent expression programs driven by transcriptional regulators promoting lineage plasticity and HOXB5, HOXB6 and NR1D2 (refs. ). Additionally, a subset of patients had high expression of dysfunction markers on cytotoxic CD8 T cells undergoing clonal expansion following enzalutamide treatment. Collectively, the transcriptional characterization of cancer and immune cells from human metastatic castration-resistant prostate cancer provides a basis for the development of therapeutic approaches complementing androgen signaling inhibition.
|Year of Publication||
R01 CA227388 / CA / NCI NIH HHS / United States
T32 GM008313 / GM / NIGMS NIH HHS / United States
K08 CA222663 / CA / NCI NIH HHS / United States
T32 CA009172 / CA / NCI NIH HHS / United States
K08 CA234458 / CA / NCI NIH HHS / United States
U01 CA233100 / CA / NCI NIH HHS / United States
R01 CA223484 / CA / NCI NIH HHS / United States
R37 CA241486 / CA / NCI NIH HHS / United States
HHMI / Howard Hughes Medical Institute / United States