Passenger deletions generate therapeutic vulnerabilities in cancer |
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Authors: | Florian L Muller Simona Colla Elisa Aquilanti Veronica E Manzo Giannicola Genovese Jaclyn Lee Daniel Eisenson Rujuta Narurkar Pingna Deng Luigi Nezi Michelle A Lee Baoli Hu Jian Hu Ergun Sahin Derrick Ong Eliot Fletcher-Sananikone Dennis Ho Lawrence Kwong Cameron Brennan Y Alan Wang Lynda Chin Ronald A DePinho |
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Institution: | Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. |
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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. |
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