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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We thank K. Ligon, C. Maire, D. N. Louis, J. Kim and G. Mohapatra for sharing bioinformatics data from their tumour neurosphere banks. We also thank D. Bigner for sharing the D423-MG and D502-MG cell lines and D. N. Louis and J. Kim for sharing the Gli56 cell line. We thank G. Chu and D. Jakubosky for assistance with necropsy and histopathological analysis. F.L.M. was supported by a training grant from the National Institutes of Health (NIH T32-CA009361) and a fellowship from the American Cancer Society (115992-PF-08-261-01-TBE). S.C. was supported by a Dana-Farber Cancer Institute/Harvard Cancer Center Myeloma SPORE career development grant. E.A. was supported by a Howard Hughes Medical Institute Medical Research Fellowship (57006984). V.M. was supported by a Harvard PRISE fellowship. M.A.L. was supported by a Diversity in Health-Related research award (3 P01 CA095616-08S1). F.L.M. thanks J. Mohr for assistance with figure preparations. We also thank K. Muller for assistance with manuscript editing. We thank all members of the DePinho and Chin laboratories for suggestions and discussions. This work is supported by the NIH (P01CA95616 to C.B., L.C. and R.A.D.) and by the Ben and Catherine Ivy Foundation (to R.A.D. and L.C.).
The authors declare no competing financial interests.
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Muller, F., Colla, S., Aquilanti, E. et al. Passenger deletions generate therapeutic vulnerabilities in cancer. Nature 488, 337–342 (2012). https://doi.org/10.1038/nature11331
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