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Passenger deletions generate therapeutic vulnerabilities in cancer
Open accessAbstract
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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“Similarly, the gene encoding enolase 1 (ENO1) is on the tumor-suppressor locus 1p36, and undergoes homozygous deletion in 1–5% of GBM cancers. Knockdown of enolase 2 (ENO2) in ENO1-null GBM cells resulted in significant inhibition of proliferation and intracranial tumorigenesis, whereas ENO1 expressing cancer cells were insensitive to ENO2 ablation.”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Muller et al., 2012
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“Furthermore, ENO1 loss results in extreme sensitivity to the pan-enolase inhibitor phosphonoacetohydroxamate (PHAH) and SF2312 (Leonard et al., 2016; Muller et al., 2012).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Muller et al., 2012
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Metadata
- Authors
- 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., Wang, Y. A., Chin, L., & DePinho, R. A.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Dana-Farber Cancer Institute (US)
- Harvard University (US)
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- DePinho, Ronald A.
- ORCID
- Venue
- Nature
- Published
- 2012-08-15
- Volume
- 488
- Issue
- 7411
- Pages
- 337-342
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3712624
- OpenAlex
- W1982318323
- Cited by
- 339
- References
- 38
- Citations by year
- 2026: 12 · 2025: 20 · 2024: 20 · 2023: 20 · 2022: 32 · 2021: 34 · 2020: 32 · 2019: 32 · 2018: 20 · 2017: 27 · 2016: 18 · 2015: 19 · 2014: 33 · 2013: 14 · 2012: 6
- FWCI
- 7.62
- Type
- journal article
- Language
- en
- Update notices
- correction (2015-07-08)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute (57006984)
- National Eye Institute (R01EY020641)
- National Cancer Institute (P01 CA 95616, T32CA009361, P01CA095616)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- alpha-enolase, neuron-specific enolase, enolase, 1p36 deletion, glioblastoma, housekeeping genes, glycolysis, RNA interference, tumor suppressor, cancer therapy
- MeSH terms
- Animals, Antineoplastic Agents, Brain Neoplasms, Chromosomes, Human, Pair 1, DNA-Binding Proteins, Enzyme Inhibitors, Glioblastoma, Homozygote, Humans, Hydroxamic Acids, Neoplasm Transplantation, Phosphonoacetic Acid, Phosphopyruvate Hydratase, Biomarkers, Tumor, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor, Sequence Deletion, Genes, Essential, Tumor Suppressor Proteins, RNA, Small Interfering, Cell Line, Tumor, Cell Proliferation, Mice, Gene Knockdown Techniques, Molecular Targeted Therapy
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