Passenger Deletions Generate Therapeutic Vulnerabilities in Cancer

Nature. 2012 Aug 16;488(7411):337-42. doi: 10.1038/nature11331.

Abstract

Inactivation of tumour-suppressor genes by homozygous deletion is a prototypic event in the cancer genome, yet such deletions often encompass neighbouring genes. We propose that homozygous deletions in such passenger genes can expose cancer-specific therapeutic vulnerabilities when the collaterally deleted gene is a member of a functionally redundant family of genes carrying out an essential function. The glycolytic gene enolase 1 (ENO1) in the 1p36 locus is deleted in glioblastoma (GBM), which is tolerated by the expression of ENO2. Here we show that short-hairpin-RNA-mediated silencing of ENO2 selectively inhibits growth, survival and the tumorigenic potential of ENO1-deleted GBM cells, and that the enolase inhibitor phosphonoacetohydroxamate is selectively toxic to ENO1-deleted GBM cells relative to ENO1-intact GBM cells or normal astrocytes. The principle of collateral vulnerability should be applicable to other passenger-deleted genes encoding functionally redundant essential activities and provide an effective treatment strategy for cancers containing such genomic events.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Biomarkers, Tumor / deficiency
  • Biomarkers, Tumor / genetics
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / genetics*
  • Brain Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Chromosomes, Human, Pair 1 / genetics
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • Enzyme Inhibitors
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Genes, Essential / genetics*
  • Genes, Tumor Suppressor
  • Glioblastoma / drug therapy*
  • Glioblastoma / genetics*
  • Glioblastoma / pathology
  • Homozygote
  • Humans
  • Hydroxamic Acids / pharmacology
  • Hydroxamic Acids / therapeutic use
  • Mice
  • Molecular Targeted Therapy / methods*
  • Neoplasm Transplantation
  • Phosphonoacetic Acid / analogs & derivatives
  • Phosphonoacetic Acid / pharmacology
  • Phosphonoacetic Acid / therapeutic use
  • Phosphopyruvate Hydratase / antagonists & inhibitors
  • Phosphopyruvate Hydratase / deficiency
  • Phosphopyruvate Hydratase / genetics
  • Phosphopyruvate Hydratase / metabolism
  • RNA, Small Interfering / genetics
  • Sequence Deletion / genetics*
  • Tumor Suppressor Proteins / deficiency
  • Tumor Suppressor Proteins / genetics

Substances

  • Antineoplastic Agents
  • Biomarkers, Tumor
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Hydroxamic Acids
  • RNA, Small Interfering
  • Tumor Suppressor Proteins
  • phosphonoacetohydroxamate
  • ENO1 protein, human
  • Phosphopyruvate Hydratase
  • Phosphonoacetic Acid