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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 Statement MAR 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)

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