Passenger Deletions Generate Therapeutic Vulnerabilities in Cancer

Inactivation of tumor suppressor genes via homozygous deletion is a prototypic event in the cancer genome, yet such deletions often encompass neighboring genes. We hypothesized that homozygous deletions in such passenger genes can expose cancer-specific therapeutic vulnerabilities in the case where the collaterally deleted gene is a member of a functionally redundant family of genes exercising an essential function. The glycolytic gene Enolase 1 (ENO1) in the 1p36 locus is deleted in Glioblastoma (GBM), which is tolerated by expression of ENO2. We demonstrate that shRNA-mediated extinction of ENO2 selectively inhibits growth, survival, and tumorigenic potential of ENO1-deleted GBM cells and that the enolase inhibitor phosphonoacetohydroxamate (PhAH) 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 harboring such genomic events.