Identification of transcriptional network disruptions in drug-resistant prostate cancer with TraRe

Metastatic castration-resistant prostate cancer (mCRPC) presents very low survival rates due to lack of response or acquired resistance to the available therapies. To date no molecular mechanisms of resistance have been identified, pointing out their complex dynamics. To identify key genes and processes associated with phenotypically-driven regulatory differences, we developed TraRe, a computational method that provides a three-tier analysis: i) at the network level, inferring differentially regulated modules; ii) at the regulon level, identifying regulatory relationships linked to phenotypic differences; and iii) at the single gene level, identifying TFs consistently linked to rewired modules. We applied TraRe (available in Bioconductor with full documentation) to transcriptomic data from 46 mCRPC patients with Abiraterone-response clinical data and uncovered abrogated immune response regulatory modules that showed strong differential regulation in Abi-resistant patients. These modules were replicated in an independent mCRPC study. Further, we experimentally validated key rewiring predictions and their associated transcription factors. Among them, ELK3, MXD1, and MYB were found to have a differential role in cell survival for Abi-response-specific settings. Moreover, we identified the role of ELK3 in cell migration capacity, which could have direct impact on mCRPC. Collectively, these findings shed light on the underlying regulatory mechanisms driving abiraterone response.