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 and Ronald A. DePinho ()
Additional contact information
Florian L. Muller: University of Texas MD Anderson Cancer Center
Simona Colla: University of Texas MD Anderson Cancer Center
Elisa Aquilanti: Dana-Farber Cancer Institute
Veronica E. Manzo: Dana-Farber Cancer Institute
Giannicola Genovese: University of Texas MD Anderson Cancer Center
Jaclyn Lee: Dana-Farber Cancer Institute
Daniel Eisenson: Dana-Farber Cancer Institute
Rujuta Narurkar: Dana-Farber Cancer Institute
Pingna Deng: University of Texas MD Anderson Cancer Center
Luigi Nezi: University of Texas MD Anderson Cancer Center
Michelle A. Lee: Dana-Farber Cancer Institute
Baoli Hu: University of Texas MD Anderson Cancer Center
Jian Hu: University of Texas MD Anderson Cancer Center
Ergun Sahin: Dana-Farber Cancer Institute
Derrick Ong: University of Texas MD Anderson Cancer Center
Eliot Fletcher-Sananikone: University of Texas MD Anderson Cancer Center
Dennis Ho: Dana-Farber Cancer Institute
Lawrence Kwong: University of Texas MD Anderson Cancer Center
Cameron Brennan: Memorial Sloan Kettering Cancer Center
Y. Alan Wang: University of Texas MD Anderson Cancer Center
Lynda Chin: University of Texas MD Anderson Cancer Center
Ronald A. DePinho: Dana-Farber Cancer Institute

Nature, 2012, vol. 488, issue 7411, 337-342

Abstract: 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.

Date: 2012
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DOI: 10.1038/nature11331

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