Reprogramming of the FOXA1 cistrome in treatment-emergent neuroendocrine prostate cancer

Sylvan C. Baca, David Y. Takeda, Ji-Heui Seo, Justin Hwang, Sheng Yu Ku, Rand Arafeh, Taylor Arnoff, Supreet Agarwal, Connor Bell, Edward O’Connor, Xintao Qiu, Sarah Abou Alaiwi, Rosario I. Corona, Marcos A. S. Fonseca, Claudia Giambartolomei, Paloma Cejas, Klothilda Lim, Monica He, Anjali Sheahan, Amin Nassar, Jacob E. Berchuck, Lisha Brown, Holly M. Nguyen, Ilsa M. Coleman, Arja Kaipainen, Navonil De Sarkar, Peter S. Nelson, Colm Morrissey, Keegan Korthauer, Mark M. Pomerantz, Leigh Ellis, Bogdan Pasaniuc, Kate Lawrenson, Kathleen Kelly, Amina Zoubeidi, William C. Hahn, Himisha Beltran, Henry W. Long, Myles Brown, Eva Corey and Matthew L. Freedman ()
Additional contact information
Sylvan C. Baca: Department of Medical Oncology, Dana-Farber Cancer Institute
David Y. Takeda: Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer Research, National Cancer Institute, NIH
Ji-Heui Seo: Department of Medical Oncology, Dana-Farber Cancer Institute
Justin Hwang: Department of Medical Oncology, Dana-Farber Cancer Institute
Sheng Yu Ku: Department of Medical Oncology, Dana-Farber Cancer Institute
Rand Arafeh: Department of Medical Oncology, Dana-Farber Cancer Institute
Taylor Arnoff: Department of Medical Oncology, Dana-Farber Cancer Institute
Supreet Agarwal: Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer Research, National Cancer Institute, NIH
Connor Bell: Department of Medical Oncology, Dana-Farber Cancer Institute
Edward O’Connor: Department of Medical Oncology, Dana-Farber Cancer Institute
Xintao Qiu: Department of Medical Oncology, Dana-Farber Cancer Institute
Sarah Abou Alaiwi: Department of Medical Oncology, Dana-Farber Cancer Institute
Rosario I. Corona: Department of Obstetrics and Gynecology and the Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center
Marcos A. S. Fonseca: Department of Obstetrics and Gynecology and the Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center
Claudia Giambartolomei: University of California Los Angeles
Paloma Cejas: Department of Medical Oncology, Dana-Farber Cancer Institute
Klothilda Lim: Department of Medical Oncology, Dana-Farber Cancer Institute
Monica He: Department of Medical Oncology, Dana-Farber Cancer Institute
Anjali Sheahan: Department of Oncologic Pathology, Dana-Farber Cancer Institute
Amin Nassar: Department of Medical Oncology, Dana-Farber Cancer Institute
Jacob E. Berchuck: Department of Medical Oncology, Dana-Farber Cancer Institute
Lisha Brown: University of Washington
Holly M. Nguyen: University of Washington
Ilsa M. Coleman: Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center
Arja Kaipainen: Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center
Navonil De Sarkar: Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center
Peter S. Nelson: Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center
Colm Morrissey: University of Washington
Keegan Korthauer: Department of Data Sciences, Dana-Farber Cancer Institute
Mark M. Pomerantz: Department of Medical Oncology, Dana-Farber Cancer Institute
Leigh Ellis: Department of Oncologic Pathology, Dana-Farber Cancer Institute
Bogdan Pasaniuc: University of California Los Angeles
Kate Lawrenson: Department of Obstetrics and Gynecology and the Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center
Kathleen Kelly: Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer Research, National Cancer Institute, NIH
Amina Zoubeidi: Vancouver Prostate Centre
William C. Hahn: Department of Medical Oncology, Dana-Farber Cancer Institute
Himisha Beltran: Department of Medical Oncology, Dana-Farber Cancer Institute
Henry W. Long: Department of Medical Oncology, Dana-Farber Cancer Institute
Myles Brown: Department of Medical Oncology, Dana-Farber Cancer Institute
Eva Corey: University of Washington
Matthew L. Freedman: Department of Medical Oncology, Dana-Farber Cancer Institute

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract Lineage plasticity, the ability of a cell to alter its identity, is an increasingly common mechanism of adaptive resistance to targeted therapy in cancer. An archetypal example is the development of neuroendocrine prostate cancer (NEPC) after treatment of prostate adenocarcinoma (PRAD) with inhibitors of androgen signaling. NEPC is an aggressive variant of prostate cancer that aberrantly expresses genes characteristic of neuroendocrine (NE) tissues and no longer depends on androgens. Here, we investigate the epigenomic basis of this resistance mechanism by profiling histone modifications in NEPC and PRAD patient-derived xenografts (PDXs) using chromatin immunoprecipitation and sequencing (ChIP-seq). We identify a vast network of cis-regulatory elements (N~15,000) that are recurrently activated in NEPC. The FOXA1 transcription factor (TF), which pioneers androgen receptor (AR) chromatin binding in the prostate epithelium, is reprogrammed to NE-specific regulatory elements in NEPC. Despite loss of dependence upon AR, NEPC maintains FOXA1 expression and requires FOXA1 for proliferation and expression of NE lineage-defining genes. Ectopic expression of the NE lineage TFs ASCL1 and NKX2-1 in PRAD cells reprograms FOXA1 to bind to NE regulatory elements and induces enhancer activity as evidenced by histone modifications at these sites. Our data establish the importance of FOXA1 in NEPC and provide a principled approach to identifying cancer dependencies through epigenomic profiling.

Date: 2021
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DOI: 10.1038/s41467-021-22139-7

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