DNA topoisomerase IIß inhibition blocks DNA end resection and synergizes with PARPi in BRCA1-deficient models

Area of Science:

• Molecular Biology
• Cancer Research
• Genetics

Background:

• DNA end resection is crucial for chromosome repair and is tightly regulated.
• Dysregulation of DNA end resection impacts cell survival, particularly under cytotoxic chemotherapy.
• Small molecules offer potential for modulating DNA repair pathways.

Purpose of the Study:

• To identify small molecules affecting DNA end resection.
• To elucidate the mechanism of action of merbarone, a DNA topoisomerase II inhibitor.
• To investigate the role of topoisomerase IIβ in DNA break processing and its implications for cancer therapy.

Main Methods:

• Identification of small molecules impacting DNA end resection.
• Mode of action studies for merbarone, including its interaction with G4 quadruplexes.
• Cellular models to assess sensitivity of BRCA1-deficient and mutant cells to merbarone and PARP inhibitors.
• In vivo studies using patient-derived xenograft (PDX) models.

Main Results:

• Merbarone affects DNA end resection and highlights a role for topoisomerase IIβ.
• Merbarone's efficacy is influenced by G4 quadruplex formation.
• BRCA1-deficient cancer cells exhibit sensitivity to merbarone.
• BRCA1 exon 11 mutant cells, resistant to PARP inhibitors (PARPi), are sensitive to merbarone and PARPi combination therapy.
• Combination therapy showed a mild antitumor effect in a PARPi-resistant PDX model with a BRCA1 exon 11 mutation.

Conclusions:

• Merbarone represents a novel therapeutic agent targeting DNA repair in cancer.
• Targeting topoisomerase IIβ and exploiting G4 quadruplex interactions could be beneficial.
• Combination therapy with merbarone and PARPi demonstrates potential for overcoming PARPi resistance in BRCA1-mutated cancers.