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- Title
Passenger deletions generate therapeutic vulnerabilities in cancer.
- Authors
Muller, Florian L; Colla, Simona; Aquilanti, Elisa; Manzo, Veronica E; Genovese, Giannicola; Lee, Jaclyn; Eisenson, Daniel; Narurkar, Rujuta; Deng, Pingna; Nezi, Luigi; Lee, Michelle A; Hu, Baoli; Hu, Jian; Sahin, Ergun; Ong, Derrick; Fletcher-Sananikone, Eliot; Ho, Dennis; Kwong, Lawrence; Brennan, Cameron; Wang, Y Alan; Chin, Lynda; DePinho, Ronald A
- 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
Nature, 2012, Vol 488, Issue 7411, p337
- ISSN
1476-4687
- Publication type
Journal Article
- DOI
10.1038/nature11331