Journal
NATURE
Volume 488, Issue 7411, Pages 337-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature11331
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Funding
- National Institutes of Health (NIH) [T32-CA009361, P01CA95616]
- American Cancer Society [115992-PF-08-261-01-TBE]
- Dana-Farber Cancer Institute/Harvard Cancer Center Myeloma SPORE career development grant
- Howard Hughes Medical Institute Medical Research Fellowship [57006984]
- Harvard PRISE fellowship
- Diversity in Health-Related research award [3 P01 CA095616-08S1]
- Ben and Catherine Ivy Foundation
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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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