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

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 synergized 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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Publication Details

Journal
Journal of Clinical Investigation
Published
2024-10-22
DOI
https://doi.org/10.1172/jci165448
Citations
7
Primary Topic
Histone Deacetylase Inhibitors Research
Type
article
Field-Weighted Citation Impact
1.64

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article

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

Ming-Lun Kang, Moeez Rathore, William E. Harte, John J. Pink et al.
7 citations
Journal of Clinical Investigation
Histone Deacetylase Inhibitors Research
1.64
article

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

Ming-Lun Kang, Moeez Rathore, William E. Harte, John J. Pink, Stanton L. Gerson, Sung‐Bau Lee, E. Ricky Chan, Yan Yan, Nian-Zhe Lee, Zih-Yao Yu, Li-Hsin Cheng, Hui-Ju Tseng, Kelvin K. Tsai, Rui Wang, Wei Zhang, Wei‐Jan Huang, Yulan Qing, Ting-Yu Chang
article en
7 citations

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 synergized 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.

Journal of Clinical InvestigationVol. 134(23)
Genomics Research Center, Academia Sinica (TW), Institute of Organic Chemistry (PL), Advanced Cancer Therapeutics (US), Ohio Aerospace Institute (US), University School (US), Case Comprehensive Cancer Center, Taipei Medical University (TW), Case Western Reserve University (US)
Case Western Reserve University, Case Comprehensive Cancer Center, Case Western Reserve University, School of Medicine, Case Western Reserve University, Academia Sinica, Ministry of Science and Technology, Taiwan, Taipei Medical University, National Taiwan University, National Science and Technology Council, National Institutes of Health, Genomics Research Center, Academia Sinica
Openalex Percentile: Top 16%
Histone Deacetylase Inhibitors Research
1.64
DOIOpen Access PDFOpenAlex
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