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Targeting AURKA to induce synthetic lethality in CREBBP-deficient B-cell malignancies via attenuation of MYC expression

Abstract

Loss-of-function mutations in CREBBP, which encodes for a histone acetyltransferase, occur frequently in B-cell malignancies, highlighting CREBBP deficiency as an attractive therapeutic target. Using established isogenic cell models, we demonstrated that CREBBP-deficient cells are selectively vulnerable to AURKA inhibition. Mechanistically, we found that co-targeting CREBBP and AURKA suppressed MYC transcriptionally and post-translationally to induce replication stress and apoptosis. Inhibition of AURKA dramatically decreased MYC protein level in CREBBP-deficient cells, implying a dependency on AURKA to sustain MYC stability. Furthermore, in vivo studies showed that pharmacological inhibition of AURKA was efficacious in delaying tumor progression in CREBBP-deficient cells and was synergistic with CREBBP inhibitors in CREBBP-proficient cells. Our study sheds light on a novel synthetic lethal interaction between CREBBP and AURKA, indicating that targeting AURKA represents a potential therapeutic strategy for high-risk B-cell malignancies harboring CREBBP inactivating mutations.

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Fig. 1: B-cell lymphoma cells with shRNA induced CREBBP knockdown exhibit increased sensitivity to AURKA inhibition.
Fig. 2: Cell lines of B-cell malignancies with CREBBP inactivation shows higher sensitivity to AURKA inhibitors.
Fig. 3: The synthetic interaction of CREBBP and AURKA/AURKB can be recapitulated genetically and pharmacologically.
Fig. 4: MYC target genes were deregulated with the treatment of SGC-CBP30 and alisertib.
Fig. 5: CREBBP-deficient cells are more dependent on AURKA to maintain MYC stability.
Fig. 6: AURKA inhibitor reduced tumor growth of CREBBP-mutated B-cell malignancies.
Fig. 7: Schematic model for the synthetic lethal interaction between CREBBP and AURKA in B-cell malignancies.

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Data availability

RNA-seq and ChIP-seq data has been deposited in GEO database under project accession number: GSE211451 and GSE232330.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81972596, 81772963, 82073391, 81970176, 82170188), Guangdong Innovative and Entrepreneurial Research Team Program (2016ZT06S638, 2016ZT06S252), the Natural Science Foundation of Guangdong Province (2021A1515011131), Guangzhou Municipal Science and Technology Project (2023A04J1272), The Singapore Ministry of Health’s National Medical Research Council (NMRC-ORIRG16nov090 and NMRC-OFLCG18May0028), Tanoto Foundation Professorship in Medical Oncology, New Century International Pte Ltd and Ling Foundation. We thank Dr. Laura Pasqualucci for the human CREBBP plasmid. The key raw data generated and/or analyzed during the current study are available at Research Data Deposit public platform (www.researchdata.org.cn), with the approval number of RDDB2024933413.

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YS and JT conceived, designed, and supervised the study; YS performed the experiments; JC analyzed and interpreted the data (e.g., biostatistics, computational analysis); RX, YT, PW, LP and KXYC supported animal work; PD, YW, LL, SL and JG provided suggestions and technical support for experiments. ZY, STL, WL and BX provided key reagents for the experiments. YS and JT wrote, reviewed, and revised the manuscript. JHH, JYC, BTT, QY and CKO provided kind suggestions for the manuscript writing. All the authors have given their consent to publish this study.

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Correspondence to Jing Tan.

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Sun, Y., Chen, J., Hong, J.H. et al. Targeting AURKA to induce synthetic lethality in CREBBP-deficient B-cell malignancies via attenuation of MYC expression. Oncogene (2024). https://doi.org/10.1038/s41388-024-03065-6

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