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ResearchIn-Press PreviewCell biologyTherapeutics Open Access | 10.1172/JCI165448

Combined HDAC8 and checkpoint kinase inhibition induces tumor-selective synthetic lethality in preclinical models

Ting-Yu Chang,1 Yan Yan,2 Zih-Yao Yu,1 Moeez Rathore,2 Nian-Zhe Lee,1 Hui-Ju Tseng,1 Li-Hsin Cheng,3 Wei-Jan Huang,4 Wei Zhang,2 Ernest R. Chan,2 Yulan Qing,2 Ming-Lun Kang,5 Rui Wang,2 Kelvin K. Tsai,3 John J. Pink,2 William E. Harte,6 Stanton L. Gerson,2 and Sung-Bau Lee7

1Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan

2Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, United States of America

3Laboratory of Advanced Molecular Therapeutics, Graduate Institute of Clinic, College of Medicine, Taipei Medical University, Taipei, Taiwan

4College of Pharmacy, College of Medicine, Taipei Medical University, Taipei, Taiwan

5Genomics Research Center, Academia Sinica, Taipei, Taiwan

6Office of Translation and Innovation, Case Western Reserve University School of Medicine, Cleveland, United States of America

7​Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan

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1Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan

2Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, United States of America

3Laboratory of Advanced Molecular Therapeutics, Graduate Institute of Clinic, College of Medicine, Taipei Medical University, Taipei, Taiwan

4College of Pharmacy, College of Medicine, Taipei Medical University, Taipei, Taiwan

5Genomics Research Center, Academia Sinica, Taipei, Taiwan

6Office of Translation and Innovation, Case Western Reserve University School of Medicine, Cleveland, United States of America

7​Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan

Find articles by Yan, Y. in: JCI | PubMed | Google Scholar

1Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan

2Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, United States of America

3Laboratory of Advanced Molecular Therapeutics, Graduate Institute of Clinic, College of Medicine, Taipei Medical University, Taipei, Taiwan

4College of Pharmacy, College of Medicine, Taipei Medical University, Taipei, Taiwan

5Genomics Research Center, Academia Sinica, Taipei, Taiwan

6Office of Translation and Innovation, Case Western Reserve University School of Medicine, Cleveland, United States of America

7​Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan

Find articles by Yu, Z. in: JCI | PubMed | Google Scholar

1Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan

2Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, United States of America

3Laboratory of Advanced Molecular Therapeutics, Graduate Institute of Clinic, College of Medicine, Taipei Medical University, Taipei, Taiwan

4College of Pharmacy, College of Medicine, Taipei Medical University, Taipei, Taiwan

5Genomics Research Center, Academia Sinica, Taipei, Taiwan

6Office of Translation and Innovation, Case Western Reserve University School of Medicine, Cleveland, United States of America

7​Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan

Find articles by Rathore, M. in: JCI | PubMed | Google Scholar

1Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan

2Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, United States of America

3Laboratory of Advanced Molecular Therapeutics, Graduate Institute of Clinic, College of Medicine, Taipei Medical University, Taipei, Taiwan

4College of Pharmacy, College of Medicine, Taipei Medical University, Taipei, Taiwan

5Genomics Research Center, Academia Sinica, Taipei, Taiwan

6Office of Translation and Innovation, Case Western Reserve University School of Medicine, Cleveland, United States of America

7​Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan

Find articles by Lee, N. in: JCI | PubMed | Google Scholar

1Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan

2Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, United States of America

3Laboratory of Advanced Molecular Therapeutics, Graduate Institute of Clinic, College of Medicine, Taipei Medical University, Taipei, Taiwan

4College of Pharmacy, College of Medicine, Taipei Medical University, Taipei, Taiwan

5Genomics Research Center, Academia Sinica, Taipei, Taiwan

6Office of Translation and Innovation, Case Western Reserve University School of Medicine, Cleveland, United States of America

7​Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan

Find articles by Tseng, H. in: JCI | PubMed | Google Scholar |

1Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan

2Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, United States of America

3Laboratory of Advanced Molecular Therapeutics, Graduate Institute of Clinic, College of Medicine, Taipei Medical University, Taipei, Taiwan

4College of Pharmacy, College of Medicine, Taipei Medical University, Taipei, Taiwan

5Genomics Research Center, Academia Sinica, Taipei, Taiwan

6Office of Translation and Innovation, Case Western Reserve University School of Medicine, Cleveland, United States of America

7​Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan

Find articles by Cheng, L. in: JCI | PubMed | Google Scholar

1Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan

2Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, United States of America

3Laboratory of Advanced Molecular Therapeutics, Graduate Institute of Clinic, College of Medicine, Taipei Medical University, Taipei, Taiwan

4College of Pharmacy, College of Medicine, Taipei Medical University, Taipei, Taiwan

5Genomics Research Center, Academia Sinica, Taipei, Taiwan

6Office of Translation and Innovation, Case Western Reserve University School of Medicine, Cleveland, United States of America

7​Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan

Find articles by Huang, W. in: JCI | PubMed | Google Scholar |

1Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan

2Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, United States of America

3Laboratory of Advanced Molecular Therapeutics, Graduate Institute of Clinic, College of Medicine, Taipei Medical University, Taipei, Taiwan

4College of Pharmacy, College of Medicine, Taipei Medical University, Taipei, Taiwan

5Genomics Research Center, Academia Sinica, Taipei, Taiwan

6Office of Translation and Innovation, Case Western Reserve University School of Medicine, Cleveland, United States of America

7​Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan

Find articles by Zhang, W. in: JCI | PubMed | Google Scholar

1Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan

2Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, United States of America

3Laboratory of Advanced Molecular Therapeutics, Graduate Institute of Clinic, College of Medicine, Taipei Medical University, Taipei, Taiwan

4College of Pharmacy, College of Medicine, Taipei Medical University, Taipei, Taiwan

5Genomics Research Center, Academia Sinica, Taipei, Taiwan

6Office of Translation and Innovation, Case Western Reserve University School of Medicine, Cleveland, United States of America

7​Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan

Find articles by Chan, E. in: JCI | PubMed | Google Scholar |

1Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan

2Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, United States of America

3Laboratory of Advanced Molecular Therapeutics, Graduate Institute of Clinic, College of Medicine, Taipei Medical University, Taipei, Taiwan

4College of Pharmacy, College of Medicine, Taipei Medical University, Taipei, Taiwan

5Genomics Research Center, Academia Sinica, Taipei, Taiwan

6Office of Translation and Innovation, Case Western Reserve University School of Medicine, Cleveland, United States of America

7​Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan

Find articles by Qing, Y. in: JCI | PubMed | Google Scholar

1Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan

2Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, United States of America

3Laboratory of Advanced Molecular Therapeutics, Graduate Institute of Clinic, College of Medicine, Taipei Medical University, Taipei, Taiwan

4College of Pharmacy, College of Medicine, Taipei Medical University, Taipei, Taiwan

5Genomics Research Center, Academia Sinica, Taipei, Taiwan

6Office of Translation and Innovation, Case Western Reserve University School of Medicine, Cleveland, United States of America

7​Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan

Find articles by Kang, M. in: JCI | PubMed | Google Scholar

1Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan

2Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, United States of America

3Laboratory of Advanced Molecular Therapeutics, Graduate Institute of Clinic, College of Medicine, Taipei Medical University, Taipei, Taiwan

4College of Pharmacy, College of Medicine, Taipei Medical University, Taipei, Taiwan

5Genomics Research Center, Academia Sinica, Taipei, Taiwan

6Office of Translation and Innovation, Case Western Reserve University School of Medicine, Cleveland, United States of America

7​Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan

Find articles by Wang, R. in: JCI | PubMed | Google Scholar |

1Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan

2Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, United States of America

3Laboratory of Advanced Molecular Therapeutics, Graduate Institute of Clinic, College of Medicine, Taipei Medical University, Taipei, Taiwan

4College of Pharmacy, College of Medicine, Taipei Medical University, Taipei, Taiwan

5Genomics Research Center, Academia Sinica, Taipei, Taiwan

6Office of Translation and Innovation, Case Western Reserve University School of Medicine, Cleveland, United States of America

7​Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan

Find articles by Tsai, K. in: JCI | PubMed | Google Scholar

1Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan

2Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, United States of America

3Laboratory of Advanced Molecular Therapeutics, Graduate Institute of Clinic, College of Medicine, Taipei Medical University, Taipei, Taiwan

4College of Pharmacy, College of Medicine, Taipei Medical University, Taipei, Taiwan

5Genomics Research Center, Academia Sinica, Taipei, Taiwan

6Office of Translation and Innovation, Case Western Reserve University School of Medicine, Cleveland, United States of America

7​Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan

Find articles by Pink, J. in: JCI | PubMed | Google Scholar

1Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan

2Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, United States of America

3Laboratory of Advanced Molecular Therapeutics, Graduate Institute of Clinic, College of Medicine, Taipei Medical University, Taipei, Taiwan

4College of Pharmacy, College of Medicine, Taipei Medical University, Taipei, Taiwan

5Genomics Research Center, Academia Sinica, Taipei, Taiwan

6Office of Translation and Innovation, Case Western Reserve University School of Medicine, Cleveland, United States of America

7​Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan

Find articles by Harte, W. in: JCI | PubMed | Google Scholar

1Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan

2Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, United States of America

3Laboratory of Advanced Molecular Therapeutics, Graduate Institute of Clinic, College of Medicine, Taipei Medical University, Taipei, Taiwan

4College of Pharmacy, College of Medicine, Taipei Medical University, Taipei, Taiwan

5Genomics Research Center, Academia Sinica, Taipei, Taiwan

6Office of Translation and Innovation, Case Western Reserve University School of Medicine, Cleveland, United States of America

7​Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan

Find articles by Gerson, S. in: JCI | PubMed | Google Scholar |

1Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan

2Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, United States of America

3Laboratory of Advanced Molecular Therapeutics, Graduate Institute of Clinic, College of Medicine, Taipei Medical University, Taipei, Taiwan

4College of Pharmacy, College of Medicine, Taipei Medical University, Taipei, Taiwan

5Genomics Research Center, Academia Sinica, Taipei, Taiwan

6Office of Translation and Innovation, Case Western Reserve University School of Medicine, Cleveland, United States of America

7​Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan

Find articles by Lee, S. in: JCI | PubMed | Google Scholar |

Published October 22, 2024 - More info

J Clin Invest. https://doi.org/10.1172/JCI165448.
Copyright © 2024, Chang et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published October 22, 2024 - Version history
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Abstract

The elevated level of replication stress is an intrinsic characteristic of cancer cells. Targeting the mechanisms that maintain genome stability to further increase replication stress and thus induce severe genome instability has become a promising approach for cancer treatment. Here, we identify histone deacetylase 8 (HDAC8) as a drug target whose inactivation synergizes with the inhibition of checkpoint kinases to elicit substantial replication stress and compromise genome integrity selectively in cancer cells. We showed that simultaneous inhibition of HDAC8 and checkpoint kinases led to extensive replication fork collapse, irreversible cell-cycle arrest, and synergistic vulnerability in various cancer cells. The efficacy of the combination treatment was further validated in patient tumor-derived organoid (PDO) and xenograft mouse (PDX) models, providing important insights into patient-specific drug responses. Our data revealed that HDAC8 activity was essential for reducing the acetylation level of structural maintenance of chromosomes protein 3 (SMC3) ahead of replication forks and preventing R loop formation. HDAC8 inactivation resulted in slowed fork progression and checkpoint kinase activation. Our findings indicate that HDAC8 guards the integrity of the replicating genome, and the cancer-specific synthetic lethality between HDAC8 and checkpoint kinases provides a promising replication stress-targeting strategy for treating a broad range of cancers.

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  • Version 1 (October 22, 2024): In-Press Preview
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