Drug-induced epigenomic plasticity reprograms circadian rhythm regulation to drive prostate cancer towards androgen-independence.
Date
2022
Authors
Linder, S.
Hoogstraat, M.
Stelloo, S.
Eickhoff, N.
Schuurman, K.
de Barros, H.
Alkemade, M.
Bekers, E.M.
Severson, T.M.
Sanders, J.
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Journal article
Citation
Cancer Discovery, 2022; 12(9):2074-2097
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Abstract
In prostate cancer, androgen receptor (AR)–targeting agents are very effective in various disease stages. However, therapy resistance inevitably occurs, and little is known about how tumor cells adapt to bypass AR suppression. Here, we performed integrative multiomics analyses on tissues isolated before and after 3 months of AR-targeting enzalutamide monotherapy from patients with high-risk prostate cancer enrolled in a neoadjuvant clinical trial. Transcriptomic analyses demonstrated that AR inhibition drove tumors toward a neuroendocrine-like disease state. Additionally, epigenomic profiling revealed massive enzalutamide-induced reprogramming of pioneer factor FOXA1 from inactive chromatin sites toward active cis-regulatory elements that dictate prosurvival signals. Notably, treatment-induced FOXA1 sites were enriched for the circadian clock component ARNTL. Posttreatment ARNTL levels were associated with patients’ clinical outcomes, and ARNTL knockout strongly decreased prostate cancer cell growth. Our data highlight a remarkable cistromic plasticity of FOXA1 following AR-targeted therapy and revealed an acquired dependency on the circadian regulator ARNTL, a novel candidate therapeutic target. Significance: Understanding how prostate cancers adapt to AR-targeted interventions is critical for
identifying novel drug targets to improve the clinical management of treatment-resistant disease. Our
study revealed an enzalutamide-induced epigenomic plasticity toward prosurvival signaling and uncovered
the circadian regulator ARNTL as an acquired vulnerability after AR inhibition, presenting a novel
lead for therapeutic development.
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©2022 American Association for Cancer Research