DNA2 Nuclease Inhibition Confers Synthetic Lethality in Cancers with Mutant p53 and Synergizes with PARP Inhibitors

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Mutant p53 (mutp53) is common in human cancers and can impair DNA damage response pathways.
• Mutp53 interferes with ATR activation by TopBP1, creating vulnerabilities in cancer cells.
• DNA2 is crucial for DNA repair, particularly homologous recombination (HR), and is often overexpressed in cancers with mutp53.

Purpose of the Study:

• To identify and evaluate novel therapeutic strategies targeting cancers with mutant p53.
• To investigate the potential of DNA2 inhibition as a synthetic lethality approach in mutp53-bearing cancers.
• To explore the combination of DNA2 inhibitors with PARP inhibitors for enhanced anti-cancer effects.

Main Methods:

• Identification and characterization of a novel DNA2 inhibitor, d16.
• Assessment of d16's anticancer activities and its effect on cell-cycle progression and DNA repair.
• Evaluation of d16's efficacy in overcoming chemotherapy resistance in mutp53 cancer models.
• Combination studies with PARP inhibitors to assess synergistic effects.

Main Results:

• The novel inhibitor d16 exhibits significant anticancer activities and overcomes chemotherapy resistance in mutp53-bearing cancers.
• d16 treatment leads to cell-cycle arrest, primarily in S-phase, and inhibits DNA repair pathways including HR.
• Re-expression of mutp53 sensitizes cancer cells to d16-mediated ATR inhibition.
• Combination therapy with d16 and PARP inhibitors shows synergistic induction of cancer cell death.

Conclusions:

• Targeting DNA2 represents a promising synthetic lethality strategy for cancers harboring mutant p53.
• The novel DNA2 inhibitor d16 demonstrates potential as a targeted therapy for mutp53 cancers.
• Combining DNA2 inhibitors with PARP inhibitors offers a novel therapeutic approach, extending PARP inhibitor benefits beyond BRCA-mutated cancers.