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 WangLynda Chin, Ronald A. Depinho

Research output: Contribution to journalArticle

163 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)337-342
Number of pages6
JournalNature
Volume488
Issue number7411
DOIs
StatePublished - Aug 16 2012

ASJC Scopus subject areas

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    Muller, F. L., Colla, S., Aquilanti, E., Manzo, V. E., Genovese, G., Lee, J., Eisenson, D., Narurkar, R., Deng, P., Nezi, L., Lee, M. A., Hu, B., Hu, J., Sahin, E., Ong, D., Fletcher-Sananikone, E., Ho, D., Kwong, L., Brennan, C., ... Depinho, R. A. (2012). Passenger deletions generate therapeutic vulnerabilities in cancer. Nature, 488(7411), 337-342. https://doi.org/10.1038/nature11331