TY - JOUR T1 - Dual Functions of SPOP and ERG Dictate Androgen Therapy Responses in Prostate Cancer JF - bioRxiv DO - 10.1101/2020.07.08.193581 SP - 2020.07.08.193581 AU - Tiziano Bernasocchi AU - Geniver El Tekle AU - Marco Bolis AU - Azzurra Mutti AU - Arianna Vallerga AU - Laura P. Brandt AU - Filippo Spriano AU - Tanya Svinkina AU - Marita Zoma AU - Valentina Ceserani AU - Anna Rinaldi AU - Hana Janouskova AU - Daniela Bossi AU - Manuela Cavalli AU - Simone Mosole AU - Roger Geiger AU - Ze Dong AU - Cai-Guang Yang AU - Domenico Albino AU - Andrea Rinaldi AU - Peter Schraml AU - Simon Linder AU - Giuseppina M. Carbone AU - Andrea Alimonti AU - Francesco Bertoni AU - Holger Moch AU - Steven A. Carr AU - Wilbert Zwart AU - Marianna Kruithof-de Julio AU - Mark A. Rubin AU - Namrata D. Udeshi AU - Jean-Philippe P. Theurillat Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/07/08/2020.07.08.193581.abstract N2 - Driver genes with a mutually exclusive mutation pattern across tumor genomes are thought to have overlapping roles in tumorigenesis. In contrast, we show here that mutually-exclusive prostate cancer driver alterations involving the ERG transcription factor and the ubiquitin ligase adaptor SPOP are synthetic sick. At the molecular level, the incompatible cancer pathways are driven by opposing functions in SPOP. ERG up-regulates wild type SPOP to dampen androgen receptor (AR) signaling and sustain ERG activity through degradation of the bromodomain histone reader ZMYND11. Conversely, SPOP-mutant tumors stabilize ZMYND11 to repress ERG-function and enable oncogenic androgen receptor signaling. This dichotomy regulates the response to therapeutic interventions in the AR pathway. While mutant SPOP renders tumor cells susceptible to androgen deprivation therapies, ERG promotes sensitivity to high-dose androgen therapy and pharmacological inhibition of wild type SPOP. More generally, these results define a distinct class of antagonistic cancer drivers and a blueprint toward their therapeutic exploitation.Competing Interest StatementMAR is listed as a co-inventor on US and International patents in the diagnostic and 385 therapeutic fields of ETS gene fusion prostate cancers (Harvard and University of 386 Michigan) and SPOP mutations (Weill Cornell Medicine). JPT has received funding for 387 the venue of scientific conferences from Astellas, MSD, and Janssen/Cilag. The remaining 388 authors declare no competing financial interests. Correspondence and requests for 389 materials should be addressed to J.P.T. (JeanP_Theurillat@ior.iosi.ch) ER -