A Unified Transcriptional, Pharmacogenomic, and Gene Dependency Approach to Decipher the Biology, Diagnostic Markers, and Therapeutic Targets Associated with Prostate Cancer Metastasis

SIMPLE SUMMARY: This manuscript demonstrates how integrated bioinformatic and statistical reanalysis of publicly available genomic datasets can be utilized to identify molecular pathways and biomarkers that may be clinically relevant to metastatic prostate cancer (mPrCa) progression. The most notable observation is that the transition from primary prostate cancer to mPrCa is characterized by upregulation of processes associated with DNA replication, metastasis, and events regulated by the serine/threonine kinase PLK1. Moreover, our analysis also identified over-expressed genes that may be exploited for potential targeted therapeutics and minimally invasive diagnostics and monitoring of mPrCa. The primary data analyzed were two transcriptional datasets for tissues derived from normal prostate, primary prostate cancer, and mPrCa. Also incorporated in the analysis were the transcriptional, gene dependency, and drug response data for hundreds of cell lines, including those derived from prostate cancer tissues. ABSTRACT: Our understanding of metastatic prostate cancer (mPrCa) has dramatically advanced during the genomics era. Nonetheless, many aspects of the disease may still be uncovered through reanalysis of public datasets. We integrated the expression datasets for 209 PrCa tissues (metastasis, primary, normal) with expression, gene dependency (GD) (from CRISPR/cas9 screen), and drug viability data for hundreds of cancer lines (including PrCa). Comparative statistical and pathways analyses and functional annotations (available inhibitors, protein localization) revealed relevant pathways and potential (and previously reported) protein markers for minimally invasive mPrCa diagnostics. The transition from localized to mPrCa involved the upregulation of DNA replication, mitosis, and PLK1-mediated events. Genes highly upregulated in mPrCa and with very high average GD (~1) are potential therapeutic targets. We showed that fostamatinib (which can target PLK1 and other over-expressed serine/threonine kinases such as AURKA, MELK, NEK2, and TTK) is more active against cancer lines with more pronounced signatures of invasion (e.g., extracellular matrix organization/degradation). Furthermore, we identified surface-bound (e.g., ADAM15, CD276, ABCC5, CD36, NRP1, SCARB1) and likely secreted proteins (e.g., APLN, ANGPT2, CTHRC1, ADAM12) that are potential mPrCa diagnostic markers. Overall, we demonstrated that comprehensive analyses of public genomics data could reveal potentially clinically relevant information regarding mPrCa.