The USP1 Inhibitor KSQ-4279 Overcomes PARP Inhibitor Resistance in Homologous Recombination-Deficient Tumors

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Defects in DNA repair pathways, like homologous recombination (HR) deficiency, are key drivers of tumor evolution and therapeutic resistance.
• PARP inhibitors are effective in tumors with HR defects (e.g., BRCA1/2 mutations), but resistance remains a significant clinical challenge.
• Tumors with DNA repair defects often exhibit dependencies on remaining repair mechanisms.

Purpose of the Study:

• To identify novel therapeutic targets in PARP inhibitor-resistant tumors.
• To develop and evaluate a potent and selective inhibitor of ubiquitin-specific peptidase-1 (USP1) for overcoming resistance.
• To assess the efficacy of combining a USP1 inhibitor with a PARP inhibitor in preclinical models.

Main Methods:

• Identification of USP1 as a critical dependency in BRCA-mutant and HR-deficient tumors.
• Development of KSQ-4279, a first-in-class potent and selective USP1 inhibitor.
• Preclinical testing of KSQ-4279 in combination with a PARP inhibitor using patient-derived PARP-resistant models.

Main Results:

• KSQ-4279 demonstrated potent and selective inhibition of USP1.
• The combination of KSQ-4279 and a PARP inhibitor was well-tolerated in preclinical models.
• Durable tumor regression was observed in patient-derived PARP-resistant models treated with the combination therapy.

Conclusions:

• USP1 is a critical dependency in tumors with BRCA mutations and HR deficiency.
• USP1 inhibitors, such as KSQ-4279, represent a promising strategy to overcome PARP inhibitor resistance.
• Combination therapy with USP1 and PARP inhibitors warrants further clinical investigation for BRCA-mutant/HR-deficient tumors.