Passenger deletions generate therapeutic vulnerabilities in cancer

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. The ‘collateral’ homozygous deletion of essential redundant housekeeping genes in cancer genomes is shown to confer therapeutic vulnerability on cancer cells with the deletion, without affecting genomically intact normal non-cancerous cells, suggesting new therapeutic opportunities. A new type of anticancer target This Article introduces the concept of 'collateral damage' in cancer genomes as a possible basis for therapeutic strategies. Ronald DePinho and colleagues examine pairs of functionally redundant 'passenger' genes with 'housekeeping' roles, for example in cellular metabolism. They hypothesize that genetic deletions in cancer that encompass one such gene (as collateral damage caused by proximity to tumour-suppressor genes) may expose a selective vulnerability of cancer cells, but not normal cells, to pharmacological inhibition of the protein encoded by the second gene. They demonstrate this concept for the glycolytic enzymes ENO1 and ENO2. There is often homozygous deletion of the ENO1 gene on chromosome 1p36 in glioblastomas, which is shown here to render glioma cells sensitive to knockdown of ENO2 or to a small-molecule enolase inhibitor. The authors further analyse existing cancer genomics data sets for other examples of pairs of redundant housekeeping genes, one of which resides close to frequently deleted tumour-suppressor genes. They suggest that this concept may