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

Oncogene volume 43, pages 2172–2183 (2024)Cite this article

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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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Author notes

  1. These authors contributed equally: Yichen Sun, Jianfeng Chen.

Authors and Affiliations

  1. Department of Clinical Laboratory Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China

    Yichen Sun

  2. State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China

    Yichen Sun, Jianfeng Chen, Rong Xiao, Peili Wang, Peng Deng, Jiuping Gao, Yali Wang & Jing Tan

  3. Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore, Singapore

    Jing Han Hong, Bin Tean Teh, Qiang Yu & Choon Kiat Ong

  4. Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology Guangzhou, Guangzhou, China

    Yan Teng, Lu Pan, Lizhen Liu, Shini Liu & Wenyu Li

  5. Department of Colorectal Surgery, the Sixth Affiliated Hospital, Sun Yat-sen University, 510655, Guangzhou, China

    Zhaoliang Yu

  6. Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore

    Jason Yongsheng Chan

  7. Lymphoma Translational Research Laboratory, Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore, Singapore

    Kelila Xin Ye Chai & Choon Kiat Ong

  8. Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore

    Bin Tean Teh & Jing Tan

  9. Genome Institute of Singapore, A*STAR, Singapore, Singapore

    Bin Tean Teh & Qiang Yu

  10. Director’s office, National Cancer Centre Singapore, Singapore, Singapore

    Soon Thye Lim

  11. Office of Education, Duke-NUS Medical School, Singapore, Singapore

    Soon Thye Lim

  12. Department of Laboratory Medicine, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, China

    Banglao Xu

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  1. Yichen Sun
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Contributions

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 43, 2172–2183 (2024). https://doi.org/10.1038/s41388-024-03065-6

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