RT Journal Article
SR Electronic
T1 Dual Functions of SPOP and ERG Dictate Androgen Therapy Responses in Prostate Cancer
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.07.08.193581
DO 10.1101/2020.07.08.193581
A1 Bernasocchi, Tiziano
A1 El Tekle, Geniver
A1 Bolis, Marco
A1 Mutti, Azzurra
A1 Vallerga, Arianna
A1 Brandt, Laura P.
A1 Spriano, Filippo
A1 Svinkina, Tanya
A1 Zoma, Marita
A1 Ceserani, Valentina
A1 Rinaldi, Anna
A1 Janouskova, Hana
A1 Bossi, Daniela
A1 Cavalli, Manuela
A1 Mosole, Simone
A1 Geiger, Roger
A1 Dong, Ze
A1 Yang, Cai-Guang
A1 Albino, Domenico
A1 Rinaldi, Andrea
A1 Schraml, Peter
A1 Linder, Simon
A1 Carbone, Giuseppina M.
A1 Alimonti, Andrea
A1 Bertoni, Francesco
A1 Moch, Holger
A1 Carr, Steven A.
A1 Zwart, Wilbert
A1 Kruithof-de Julio, Marianna
A1 Rubin, Mark A.
A1 Udeshi, Namrata D.
A1 Theurillat, Jean-Philippe P.
YR 2020
UL http://biorxiv.org/content/early/2020/10/24/2020.07.08.193581.abstract
AB 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)