Passenger deletions generate therapeutic vulnerabilities in cancer.

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

Index: Nature 488(7411) , 337-42, (2012)

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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.