Targeting thymine DNA glycosylase induces synthetic lethality in p53-deficient cancers

Area of Science:

• Molecular Biology
• Cancer Research
• Drug Discovery

Background:

• Thymine DNA glycosylase (TDG) plays critical roles in DNA repair, demethylation, and transcription, impacting development and cancer.
• The precise mechanisms of TDG in cancer progression and its therapeutic targeting remain underexplored.

Purpose of the Study:

• To investigate the therapeutic potential of targeting TDG in cancer.
• To elucidate the molecular mechanisms underlying TDG's role in p53-deficient cancers.

Main Methods:

• Development of C-271, a novel small-molecule inhibitor targeting TDG.
• Evaluation of C-271's efficacy in preclinical cancer models.
• Mechanistic studies involving gene expression analysis and pathway activation assays (RIG-I/MDA5-MAVS).

Main Results:

• Targeting TDG with C-271 demonstrated significant therapeutic efficacy in suppressing p53-deficient tumors.
• TDG inhibition led to DHX9 downregulation and aberrant accumulation of double-stranded RNA (dsRNA) in p53-deficient cells.
• Accumulated dsRNA activated the RIG-I/MDA5-MAVS pathway, resulting in tumor suppression and enhanced anti-tumor immunity.

Conclusions:

• TDG and p53 exhibit synthetic lethality, making TDG a viable therapeutic target in p53-deficient cancers.
• C-271 represents a promising first-in-class inhibitor for p53-deficient cancers, leveraging a novel mechanism of action.
• TDG inhibition offers a potential strategy to enhance anti-tumor immunity through dsRNA-mediated pathway activation.