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
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use
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Biomarkers, Tumor / deficiency
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Biomarkers, Tumor / genetics
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Brain Neoplasms / drug therapy*
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Brain Neoplasms / genetics*
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Brain Neoplasms / pathology
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Cell Line, Tumor
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Cell Proliferation
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Chromosomes, Human, Pair 1 / genetics
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DNA-Binding Proteins / deficiency
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DNA-Binding Proteins / genetics
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Enzyme Inhibitors
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Gene Expression Regulation, Neoplastic
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Gene Knockdown Techniques
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Genes, Essential / genetics*
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Genes, Tumor Suppressor
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Glioblastoma / drug therapy*
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Glioblastoma / genetics*
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Glioblastoma / pathology
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Homozygote
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Humans
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Hydroxamic Acids / pharmacology
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Hydroxamic Acids / therapeutic use
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Mice
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Molecular Targeted Therapy / methods*
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Neoplasm Transplantation
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Phosphonoacetic Acid / analogs & derivatives
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Phosphonoacetic Acid / pharmacology
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Phosphonoacetic Acid / therapeutic use
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Phosphopyruvate Hydratase / antagonists & inhibitors
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Phosphopyruvate Hydratase / deficiency
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Phosphopyruvate Hydratase / genetics
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Phosphopyruvate Hydratase / metabolism
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RNA, Small Interfering / genetics
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Sequence Deletion / genetics*
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Tumor Suppressor Proteins / deficiency
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Tumor Suppressor Proteins / genetics
Substances
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Antineoplastic Agents
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Biomarkers, Tumor
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DNA-Binding Proteins
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Enzyme Inhibitors
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Hydroxamic Acids
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RNA, Small Interfering
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Tumor Suppressor Proteins
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phosphonoacetohydroxamate
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ENO1 protein, human
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Phosphopyruvate Hydratase
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Phosphonoacetic Acid