Identification of potential therapeutic targets in prostate cancer through a cross-species approach

EMBO Mol Med. 2018 Mar;10(3):e8274. doi: 10.15252/emmm.201708274.

Abstract

Genetically engineered mouse models of cancer can be used to filter genome-wide expression datasets generated from human tumours and to identify gene expression alterations that are functionally important to cancer development and progression. In this study, we have generated RNAseq data from tumours arising in two established mouse models of prostate cancer, PB-Cre/PtenloxP/loxP and p53loxP/loxPRbloxP/loxP, and integrated this with published human prostate cancer expression data to pinpoint cancer-associated gene expression changes that are conserved between the two species. To identify potential therapeutic targets, we then filtered this information for genes that are either known or predicted to be druggable. Using this approach, we revealed a functional role for the kinase MELK as a driver and potential therapeutic target in prostate cancer. We found that MELK expression was required for cell survival, affected the expression of genes associated with prostate cancer progression and was associated with biochemical recurrence.

Keywords: MELK; cross‐species analysis; mouse models; new cancer targets; prostate cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogenesis / drug effects
  • Carcinogenesis / genetics
  • Carcinogenesis / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Disease Progression
  • Down-Regulation / drug effects
  • Down-Regulation / genetics
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / drug effects
  • Genome
  • Humans
  • Male
  • Mice
  • Molecular Targeted Therapy*
  • Naphthyridines / pharmacology
  • Neoplasm Invasiveness
  • Phenotype
  • Phosphorylation / drug effects
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / pathology
  • Prostatic Neoplasms / therapy*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Species Specificity
  • Spindle Apparatus / drug effects
  • Spindle Apparatus / metabolism
  • Stathmin / metabolism
  • Transcriptome / genetics

Substances

  • Naphthyridines
  • STMN1 protein, human
  • Stathmin
  • MELK protein, human
  • Protein-Serine-Threonine Kinases
  • OTS167