Drug-induced epigenomic plasticity reprograms circadian rhythm regulation to drive prostate cancer towards androgen-independence.

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 multi-omics analyses on tissues isolated before and after 3 months of AR-targeting enzalutamide monotherapy from high-risk prostate cancer patients enrolled in a neoadjuvant clinical trial. Transcriptomic analyses demonstrated that AR inhibition drove tumors towards a neuroendocrine-like disease state. Additionally, epigenomic profiling revealed massive enzalutamide-induced reprogramming of pioneer factor FOXA1 - from inactive chromatin sites towards active cis-regulatory elements that dictate pro-survival signals. Notably, treatment-induced FOXA1 sites were enriched for circadian clock component ARNTL. Post-treatment ARNTL levels associated with poor outcome, 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 circadian regulator ARNTL, a novel candidate therapeutic target.

Cancer discovery. 2022 Jun 27 [Epub ahead of print]

Simon Linder, Marlous Hoogstraat, Suzan Stelloo, Nils Eickhoff, Karianne Schuurman, Hilda de Barros, Maartje Alkemade, Elise M Bekers, Tesa M Severson, Joyce Sanders, Chia-Chi Flora Huang, Tunc Morova, Umut Berkay Altintas, Liesbeth Hoekman, Yongsoo Kim, Sylvan C Baca, Martin Sjostrom, Anniek Zaalberg, Dorine C Hintzen, Jeroen de Jong, Roelof J C Kluin, Iris de Rink, Claudia Giambartolomei, Ji-Heui Seo, Bogdan Pasaniuc, Maarten Altelaar, Rene H Medema, Felix Y Feng, Amina Zoubeidi, Matthew L Freedman, Lodewyk F A Wessels, Lisa M Butler, Nathan A Lack, Henk van der Poel, Andries M Bergman, Wilbert Zwart

The Netherlands Cancer Institute, Amsterdam, North Holland, Netherlands., Netherlands Cancer Institute, Amsterdam, Netherlands., The Netherlands Cancer Institute, Amsterdam, Netherlands., The Netherlands Cancer Institute, Netherlands., University of British Columbia, Vancouver, BC, Canada., Koc University, Istanbul, Turkey., NKI, Amsterdam, Netherlands., Amsterdam UMC, Netherlands., Hungarian Academy of Sciences, Boston, United States., University of California, San Francisco, San Francisco, United States., Netherlands Cancer Institute, Netherlands., The Netherlands Cancer Institute, Amsterdam, Noord-Holland, Netherlands., Istituto Italiano di Tecnologia, Genoa, Italy., Dana-Farber Cancer Institute, BOSTON, Massachusetts, United States., David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States., NKI, Netherlands., University Medical Center Utrecht, Amsterdam, Netherlands., University of California, San Francisco, San Francisco, CA, United States., University of British Columbia, Vancouver, British Colombia, Canada., Dana-Farber Cancer Institute, Boston, MA, United States., The Netherlands Cancer Institute, Amsterdam, NH, Netherlands., University of Adelaide, School of Medicine and Freemasons Foundation Centre for Men's Health, Adelaide, SA, Australia., The Netherlands Cancer Institute, amsterdam, Netherlands.