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Genome-wide CRISPR screen uncovers a synergistic effect of combining Haspin and Aurora kinase B inhibition

Abstract

Aurora kinases are a family of serine/threonine kinases vital for cell division. Because of the overexpression of Aurora kinases in a broad range of cancers and their important roles in mitosis, inhibitors targeting Aurora kinases have attracted attention in cancer therapy. VX-680 is an effective pan-Aurora kinase inhibitor; however, its clinical efficacy was not satisfying. In this study, we performed CRISPR/Cas9 screens to identify genes whose depletion shows synthetic lethality with VX-680. The top hit from these screens was GSG2 (also known as Haspin), a serine/threonine kinase that phosphorylates histone H3 at Thr-3 during mitosis. Moreover, both Haspin knockout and Haspin inhibitor-treated HCT116 cells were hypersensitive to VX-680. Furthermore, we showed that the synthetic lethal interaction between Haspin depletion and VX-680 was mediated by the inhibition of Haspin with Aurora kinase B (AURKB), but not with Aurora kinase A (AURKA). Strikingly, combined inhibition of Haspin and AURKB had a better efficacy than single-agent treatment in both head and neck squamous cell carcinoma and non-small cell lung cancer. Taken together, our findings have uncovered a synthetic lethal interaction between AURKB and Haspin, which provides a strong rationale for this combination therapy for cancer patients.

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Fig. 1: CRSPR/Cas9-based genome-wide screens in VX-680-treated cells reveal GSG2 (also called Haspin) as the top candidate.
Fig. 2: Depletion or inhibition of Haspin sensitizes cells to VX-680 treatment.
Fig. 3: Haspin inhibitor potentiates the efficacy of AURKB inhibitor but not AURKA inhibitor.
Fig. 4: Combined inhibition of Haspin and AURKB exhibits better antitumor efficacy for HNSCC and NSCLC compared with single-agent treatment.

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Acknowledgements

We thank all the members of the Chen laboratory for their help and constructive discussions and Dr Faye M. Johnson for her suggestions regarding the experimental design. We thank Drs Jeffrey N. Myers, Faye M. Johnson, Jae-Il Park, and Glen Traver Hart for providing reagents. We also thank Bryan Tutt in Scientific Publications, Research Medical Library, the University of Texas MD Anderson Cancer Center for help with the scientific editing of the paper.

Funding

This work was supported in part by the Pamela and Wayne Garrison Distinguished Chair in Cancer Research to JC. We thank The University of Texas MD Anderson Cancer Center Science Park Next-Generation Sequencing (NGS) core Facility with CPRIT Core Facility Support Award (CPRIT RP170002). JC also received support from NIH (CA193124, CA210929).

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MH, XF and JC conceived the project. MH, XF, CW, MT and APH performed the experiments. DS, GW and TH analyzed the deep-sequencing results. MH and JC wrote the paper with input from all authors.

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Correspondence to Junjie Chen.

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Huang, M., Feng, X., Su, D. et al. Genome-wide CRISPR screen uncovers a synergistic effect of combining Haspin and Aurora kinase B inhibition. Oncogene 39, 4312–4322 (2020). https://doi.org/10.1038/s41388-020-1296-2

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