Loss of heterozygosity of essential genes represents a widespread class of potential cancer vulnerabilities

Caitlin A. Nichols, William J. Gibson, Meredith S. Brown, Jack A. Kosmicki, John P. Busanovich, Hope Wei, Laura M. Urbanski, Naomi Curimjee, Ashton C. Berger, Galen F. Gao, Andrew D. Cherniack, Sirano Dhe-Paganon, Brenton R. Paolella () and Rameen Beroukhim ()
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Caitlin A. Nichols: Departments of Cancer Biology
William J. Gibson: Broad Institute of MIT and Harvard
Meredith S. Brown: Departments of Cancer Biology
Jack A. Kosmicki: Massachusetts General Hospital and Harvard Medical School
John P. Busanovich: Departments of Cancer Biology
Hope Wei: Departments of Cancer Biology
Laura M. Urbanski: Departments of Cancer Biology
Naomi Curimjee: Departments of Cancer Biology
Ashton C. Berger: Dana-Farber Cancer Institute and Harvard Medical School
Galen F. Gao: Broad Institute of MIT and Harvard
Andrew D. Cherniack: Dana-Farber Cancer Institute and Harvard Medical School
Sirano Dhe-Paganon: Departments of Cancer Biology
Brenton R. Paolella: Departments of Cancer Biology
Rameen Beroukhim: Departments of Cancer Biology

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract Alterations in non-driver genes represent an emerging class of potential therapeutic targets in cancer. Hundreds to thousands of non-driver genes undergo loss of heterozygosity (LOH) events per tumor, generating discrete differences between tumor and normal cells. Here we interrogate LOH of polymorphisms in essential genes as a novel class of therapeutic targets. We hypothesized that monoallelic inactivation of the allele retained in tumors can selectively kill cancer cells but not somatic cells, which retain both alleles. We identified 5664 variants in 1278 essential genes that undergo LOH in cancer and evaluated the potential for each to be targeted using allele-specific gene-editing, RNAi, or small-molecule approaches. We further show that allele-specific inactivation of either of two essential genes (PRIM1 and EXOSC8) reduces growth of cells harboring that allele, while cells harboring the non-targeted allele remain intact. We conclude that LOH of essential genes represents a rich class of non-driver cancer vulnerabilities.

Date: 2020
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DOI: 10.1038/s41467-020-16399-y

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