Passenger deletions generate therapeutic vulnerabilities in cancer

摘要

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 (ENOl) in the Ip36 locus is deleted in glioblastoma (GBM), which is tolerated by the expression of ENOl. Here we show that short-hairpin-RNA-mediated silencing of ENO2 selectively inhibits growth, survival and the tumorigenic potential of ENOi-deleted GBM cells, and that the enolase inhibitor phosphonoacetohydroxamate is selectively toxic to EiVOI-deleted GBM cells relative to ENOl-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.