Purpose: Lineage plasticity in prostate cancer - most commonly exemplified by loss of androgen receptor (AR) signaling and a switch from a luminal to alternate differentiation program - is now recognized as a treatment resistance mechanism. Lineage plasticity is a spectrum, but neuroendocrine prostate cancer (NEPC) is the most virulent example. Currently, there are limited treatments for NEPC. Moreover, the incidence of treatment-emergent NEPC (t- NEPC) is increasing in the era of novel AR inhibitors. In contradistinction to de novo NEPC, t-NEPC tumors often express the AR, but AR's functional role in t-NEPC is unknown. Furthermore, targetable factors that promote t-NEPC lineage plasticity are also unclear. Experimental Design: Using an integrative systems biology approach, we investigated enzalutamide-resistant t-NEPC cell lines and their parental, enzalutamide-sensitive adenocarcinoma cell lines. The AR is still expressed in these t-NEPC cells, enabling us to determine the role of the AR and other key factors in regulating t-NEPC lineage plasticity. Results: AR inhibition accentuates lineage plasticity in t-NEPC cells - an effect not observed in parental, enzalutamide-sensitive adenocarcinoma cells. Induction of an AR-repressed, lineage plasticity program is dependent on activation of the transcription factor E2F1 in concert with the BET bromodomain chromatin reader BRD4. BET inhibition (BETi) blocks this E2F1/BRD4-regulated program and decreases growth of t-NEPC tumor models and a subset of t-NEPC patient tumors with high activity of this program in a BETi clinical trial. Conclusions: E2F1 and BRD4 are critical for activating an ARrepressed, t-NEPC lineage plasticity program. BETi is a promising approach to block this program.
CITATION STYLE
Kim, D. H., Sun, D., Storck, W. K., Leng, K. W., Jenkins, C., Coleman, D. J., … Alumkal, J. J. (2021). BET bromodomain inhibition blocks an AR-repressed, E2F1-activated treatment-emergent neuroendocrine prostate cancer lineage plasticity program. Clinical Cancer Research, 27(17), 4923–4936. https://doi.org/10.1158/1078-0432.CCR-20-4968
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