RT Journal Article
SR Electronic
T1 Genome-wide CRISPR screen reveals the synthetic lethality between BCL2L1 inhibition and radiotherapy
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202302353
DO 10.26508/lsa.202302353
VO 7
IS 4
A1 Yin, Ling
A1 Hu, Xiaoding
A1 Pei, Guangsheng
A1 Tang, Mengfan
A1 Zhou, You
A1 Zhang, Huimin
A1 Huang, Min
A1 Li, Siting
A1 Zhang, Jie
A1 Citu, Citu
A1 Zhao, Zhongming
A1 Debeb, Bisrat G
A1 Feng, Xu
A1 Chen, Junjie
YR 2024
UL https://www.life-science-alliance.org/content/7/4/e202302353.abstract
AB 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.