Abstract 3003: Loss of heterozygosity of essential genes represents a novel class of cancer vulnerabilities
| Autor: | Meredith Brown, Brenton R. Paolella, Laura M. Urbanski, Ashton C. Berger, Caitlin A. Nichols, Jack A. Kosmicki, John P. Busanovich, William J. Gibson, Galen F. Gao, Andrew D. Cherniack, Rameen Beroukhim |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Genetics Cancer Research Cancer Single-nucleotide polymorphism Biology medicine.disease Loss of heterozygosity 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Oncology RNA interference 030220 oncology & carcinogenesis Gene expression Cancer cell medicine Allele Gene |
| Zdroj: | Cancer Research. 78:3003-3003 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | Despite progress in precision cancer drug discovery, few highly selective therapies exist in the clinic, creating the need for additional therapeutic targets. We have shown that copy number alterations (CNAs) in essential genes represent novel non-driver gene vulnerabilities in cancer. Here we interrogate loss of heterozygosity (LOH) of single nucleotide polymorphisms (SNPs) located in essential genes as a novel class of candidate therapeutic targets. We hypothesized that monoallelic inactivation of the single allele retained in tumors can selectively kill cancer cells, while somatic cells, which retain both alleles, will tolerate allele-specific knockout. We identified a list of over 1000 common missense SNPs in at least 1500 essential genes that undergo LOH in cancer and performed proof-of-concept allele-specific gene inactivation in two essential genes (PRIM1 and EXOSC8) using CRISPR-Cas9. We assessed the fidelity of allele-specific gene disruption and its cellular effects on gene expression, cell growth, and cell death in LOH and non-LOH genetic contexts. We determined that allele-specific knockout of PRIM1 and EXOSC8 selectively targets cells harboring only the single targeted allele of that gene. In cells retaining only the sensitive allele, we observed decreased target gene expression and cell viability that did not occur in cells retaining the resistant allele. We conclude that allele-selective inactivation of essential genes in regions of LOH (such as PRIM1 and EXOSC8) represents a novel candidate therapeutic strategy in cancer. The corresponding class of novel non-driver cancer vulnerabilities may provide a rich source of targets for future precision therapeutic development using gene editing, RNAi, or small-molecule approaches. Citation Format: Caitlin A. Nichols, Brenton R. Paolella, William J. Gibson, Meredith S. Brown, Laura M. Urbanski, Jack A. Kosmicki, John P. Busanovich, Ashton C. Berger, Galen F. Gao, Andrew D. Cherniack, Rameen Beroukhim. Loss of heterozygosity of essential genes represents a novel class of cancer vulnerabilities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3003. |
| Databáze: | OpenAIRE |
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