Faculty, Staff and Student Publications
Genome-Wide CRISPR Screen Reveals the Synthetic Lethality between BCL2L1 Inhibition and Radiotherapy
Publication Date
4-1-2024
Journal
Life Science Alliance
Abstract
Radiation therapy (RT) is one of the most commonly used anticancer therapies. However, the landscape of cellular response to irradiation, especially to a single high-dose irradiation, remains largely unknown. In this study, we performed a whole-genome CRISPR loss-of-function screen and revealed temporal inherent and acquired responses to RT. Specifically, we found that loss of the IL1R1 pathway led to cellular resistance to RT. This is in part because of the involvement of radiation-induced IL1R1-dependent transcriptional regulation, which relies on the NF-κB pathway. Moreover, the mitochondrial anti-apoptotic pathway, particularly the BCL2L1 gene, is crucially important for cell survival after radiation. BCL2L1 inhibition combined with RT dramatically impeded tumor growth in several breast cancer cell lines and syngeneic models. Taken together, our results suggest that the combination of an apoptosis inhibitor such as a BCL2L1 inhibitor with RT may represent a promising anticancer strategy for solid cancers including breast cancer.
Keywords
Female, Humans, bcl-X Protein, Breast Neoplasms, Cell Line, Tumor, Clustered Regularly Interspaced Short Palindromic Repeats, NF-kappa B, Synthetic Lethal Mutations
DOI
10.26508/lsa.202302353
PMID
38316463
PMCID
PMC10844523
PubMedCentral® Posted Date
February 2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genomics Commons, Medical Genetics Commons, Molecular Genetics Commons, Oncology Commons
Comments
Supplementary Material
PMID: 38316463