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

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Cancer cells exhibit elevated replication stress, making them vulnerable to further genomic instability.
• Targeting genome stability mechanisms is a promising cancer treatment strategy.
• Histone deacetylase 8 (HDAC8) is explored as a potential drug target.

Purpose of the Study:

• To identify HDAC8 as a drug target that synergizes with checkpoint kinase inhibition.
• To investigate the combined effect of HDAC8 and checkpoint kinase inhibition on cancer cell genome integrity.
• To validate the efficacy of this combination therapy in preclinical models.

Main Methods:

• Inhibition of HDAC8 and checkpoint kinases in various cancer cell lines.
• Assessment of replication fork collapse, cell-cycle arrest, and genome instability.
• Validation in patient tumor-derived organoid (PDO) and patient-derived xenograft (PDX) mouse models.
• Analysis of HDAC8's role in regulating SMC3 acetylation and R loop formation.

Main Results:

• Simultaneous inhibition of HDAC8 and checkpoint kinases induced substantial replication stress and compromised genome integrity selectively in cancer cells.
• This combination led to extensive replication fork collapse, irreversible cell-cycle arrest, and synergistic vulnerability.
• HDAC8 inactivation was shown to slow fork progression and activate checkpoint kinases by affecting SMC3 acetylation and R loop formation.
• Therapeutic efficacy was confirmed in PDO and PDX models, highlighting patient-specific responses.

Conclusions:

• HDAC8 plays a crucial role in maintaining replicating genome integrity.
• The synthetic lethality between HDAC8 and checkpoint kinases offers a cancer-specific targeting strategy.
• This approach holds promise for treating a broad spectrum of cancers by inducing replication stress.