Phenotypic plasticity is a hallmark of cancer and increasingly realized as a mechanism of resistance to androgen receptor (AR)-targeted therapy. Now that many prostate cancer (PCa) patients are treated upfront with AR-targeted agents, it's critical to identify actionable mechanisms that drive phenotypic plasticity, to prevent the emergence of resistance. We showed that loss of tristetraprolin (TTP, gene ZFP36) increased NF-κB activation, and was associated with higher rates of aggressive disease and early recurrence in primary PCa. We also examined the clinical and biological impact of ZFP36 loss with co-loss of PTEN, a known driver of PCa. Analysis of multiple independent primary PCa cohorts demonstrated that PTEN and ZFP36 co-loss was associated with increased recurrence risk. Engineering prostate-specific Zfp36 deletion in vivo, induced prostatic intraepithelial neoplasia, and, with Pten co-deletion, resulted in rapid progression to castration-resistant adenocarcinoma. Zfp36 loss altered the cell state driven by Pten loss, demonstrated by enrichment of EMT, inflammation, TNFα/NF-κB, IL6-JAK/STAT3 gene sets. Additionally, our work revealed that ZFP36 loss also induced enrichment of multiple gene sets involved in mononuclear cell migration, chemotaxis, and proliferation. Use of the NF-κB inhibitor, dimethylaminoparthenolide (DMAPT) induced marked therapeutic responses in tumors with PTEN and ZFP36 co-loss and reversed castration resistance.
The Journal of clinical investigation. 2024 Nov 19 [Epub ahead of print]
Katherine L Morel, Beatriz Germán, Anis A Hamid, Jagpreet S Nanda, Simon Linder, Andries M Bergman, Henk van der Poel, Ingrid Hofland, Elise M Bekers, Shana Y Trostel, Deborah L Burkhart, Scott Wilkinson, Anson T Ku, Minhyung Kim, Jina Kim, Duanduan Ma, Jasmine T Plummer, Sungyong You, Xiaofeng A Su, Wilbert Zwart, Adam G Sowalsky, Christopher J Sweeney, Leigh Ellis
South Australian Immunogenomics Cancer Institute, University of Adelaide, Adelaide, Australia., Center for Prostate Disease Research, Uniformed Services University of the Health Sciences, Bethesda, United States of America., Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States of America., Division of Hematology and Oncology Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America., Division of Oncogenomics, Oncode Institute, Netherlands Cancer Institute, Amsterdam, Netherlands., Division of Urology, Netherlands Cancer Institute, Amsterdam, Netherlands., Core Facility Molecular Pathology and Biobanking, Netherlands Cancer Institute, Amsterdam, Netherlands., Division of Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands., Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America., Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, United States of America., David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, United States of America., Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, United States of America., Division of Oncogenomics, Oncode Institute, Netheralnds Cancer Institute, Amsterdam, Netherlands.