Cross-species identification of PIP5K1-, splicing- and ubiquitin-related pathways as potential targets for RB1-deficient cells

PLoS Genet. 2021 Feb 16;17(2):e1009354. doi: 10.1371/journal.pgen.1009354. eCollection 2021 Feb.

Abstract

The RB1 tumor suppressor is recurrently mutated in a variety of cancers including retinoblastomas, small cell lung cancers, triple-negative breast cancers, prostate cancers, and osteosarcomas. Finding new synthetic lethal (SL) interactions with RB1 could lead to new approaches to treating cancers with inactivated RB1. We identified 95 SL partners of RB1 based on a Drosophila screen for genetic modifiers of the eye phenotype caused by defects in the RB1 ortholog, Rbf1. We validated 38 mammalian orthologs of Rbf1 modifiers as RB1 SL partners in human cancer cell lines with defective RB1 alleles. We further show that for many of the RB1 SL genes validated in human cancer cell lines, low activity of the SL gene in human tumors, when concurrent with low levels of RB1 was associated with improved patient survival. We investigated higher order combinatorial gene interactions by creating a novel Drosophila cancer model with co-occurring Rbf1, Pten and Ras mutations, and found that targeting RB1 SL genes in this background suppressed the dramatic tumor growth and rescued fly survival whilst having minimal effects on wild-type cells. Finally, we found that drugs targeting the identified RB1 interacting genes/pathways, such as UNC3230, PYR-41, TAK-243, isoginkgetin, madrasin, and celastrol also elicit SL in human cancer cell lines. In summary, we identified several high confidence, evolutionarily conserved, novel targets for RB1-deficient cells that may be further adapted for the treatment of human cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Cell Line, Tumor
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / metabolism
  • Eye Abnormalities / genetics
  • Eye Abnormalities / metabolism
  • Humans
  • Neoplasms / genetics*
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism
  • Phosphotransferases (Alcohol Group Acceptor) / genetics*
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • RNA Interference
  • RNA Splicing*
  • Retinoblastoma Protein / deficiency
  • Retinoblastoma Protein / genetics*
  • Retinoblastoma Protein / metabolism
  • Signal Transduction*
  • Species Specificity
  • Survival Analysis
  • Synthetic Lethal Mutations / genetics
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Ubiquitin / metabolism*
  • ras Proteins / genetics
  • ras Proteins / metabolism

Substances

  • Drosophila Proteins
  • Rbf protein, Drosophila
  • Retinoblastoma Protein
  • Transcription Factors
  • Ubiquitin
  • Phosphotransferases (Alcohol Group Acceptor)
  • 1-phosphatidylinositol-4-phosphate 5-kinase
  • PTEN Phosphohydrolase
  • ras Proteins