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.

Brain metastases from lung adenocarcinoma (BM-LUAD) cause significant patient mortality. To identify genomic alterations that promote brain metastases, we performed whole-exome sequencing of 73 BM-LUAD cases. Using case-control analyses, we discovered candidate drivers of brain metastasis by identifying genes with more frequent copy-number aberrations in BM-LUAD compared to 503 primary lung adenocarcinomas. We identified three regions with significantly higher amplification frequencies in BM-LUAD, including MYC (12% vs 6%), YAP1 (7% vs 0.8%), and MMP13 (10% vs 0.6%) and significantly more frequent deletions in CDKN2A/B (27% vs 13%). We confirmed that amplification frequencies of MYC and YAP1 / MMP13 were elevated in an independent cohort of 105 patients. Functional assessment in patient-derived xenograft mouse models validated that MYC , YAP1 or MMP13 overexpression increased the brain metastasis incidence. These results demonstrate that somatic alterations contribute to brain metastases and that genomic sequencing of a large number of metastatic tumors can reveal novel metastatic drivers.