TY - JOUR
T1 - Genome-wide CRISPR screen reveals the synthetic lethality between BCL2L1 inhibition and radiotherapy
AU - Yin, Ling
AU - Hu, Xiaoding
AU - Pei, Guangsheng
AU - Tang, Mengfan
AU - Zhou, You
AU - Zhang, Huimin
AU - Huang, Min
AU - Li, Siting
AU - Zhang, Jie
AU - Citu, Citu
AU - Zhao, Zhongming
AU - Debeb, Bisrat G.
AU - Feng, Xu
AU - Chen, Junjie
N1 - Publisher Copyright:
© 2024, Life Science Alliance, LLC. All rights reserved.
PY - 2024/4
Y1 - 2024/4
N2 - Radiation therapy (RT) is one of the most commonly used anti-cancer 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.
AB - Radiation therapy (RT) is one of the most commonly used anti-cancer 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.
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U2 - 10.26508/lsa.202302353
DO - 10.26508/lsa.202302353
M3 - Article
C2 - 38316463
AN - SCOPUS:85184415903
SN - 2575-1077
VL - 7
JO - Life science alliance
JF - Life science alliance
IS - 4
M1 - e202302353
ER -