Understanding Synthetic Sick Interactions of Prostate Cancer Driver Genes

Genetic aberrations in multiple driver genes co-operate in tumorigenesis and affect therapeutic outcomes. While this concept has been extensively studied and confirmed in the last decades, little is known about the interplay of driver mutations that never co-occur with each other in the very same cancer cells. Comprehensive cancer genome characterization has revealed that recurrent gene fusions involving the oncogenic ETS transcription factor ERG and point mutations in the ubiquitin ligase adaptor SPOP are distributed in a strictly mutually exclusive manner across prostate cancer genomes. However, the underlying basis of this observation is unknown. Our preliminary data indicate that recurrent ERG gene fusions and SPOP point mutants - even though oncogenic on their own - are together synthetic sick. The outlined project aims to (i) further characterize the synthetic sick interaction in vivo and (ii) delineate its underlying molecular mechanism. The gathered insights may give an explanation to the exquisite distribution of recurrent mutations in SPOP and ERG across prostate cancer genomes and may lay the foundation to innovative therapeutic approaches to fight tumors characterized by recurrent genetic aberrations in ERG or SPOP.