AI Article Synopsis

  • Defects in DNA repair pathways, particularly in BRCA1 or BRCA2, contribute to tumor evolution and resistance to therapies like PARP inhibitors, creating vulnerabilities in tumors.
  • Researchers identified USP1 as a key target in BRCA-mutant tumors and developed KSQ-4279, the first selective USP1 inhibitor being tested clinically.
  • The combination of KSQ-4279 and PARP inhibitors showed promise by effectively reducing tumors resistant to PARP treatment, suggesting a new strategy for improving outcomes in patients with HR-deficient tumors.

Article Abstract

Defects in DNA repair pathways play a pivotal role in tumor evolution and resistance to therapy. At the same time, they create vulnerabilities that render tumors dependent on the remaining DNA repair processes. This phenomenon is exemplified by the clinical activity of PARP inhibitors in tumors with homologous recombination (HR) repair defects, such as tumors with inactivating mutations in BRCA1 or BRCA2. However, the development of resistance to PARP inhibitors in BRCA-mutant tumors represents a high unmet clinical need. In this study, we identified deubiquitinase ubiquitin-specific peptidase-1 (USP1) as a critical dependency in tumors with BRCA mutations or other forms of HR deficiency and developed KSQ-4279, the first potent and selective USP1 inhibitor to enter clinical testing. The combination of KSQ-4279 with a PARP inhibitor was well tolerated and induced durable tumor regression across several patient-derived PARP-resistant models. These findings indicate that USP1 inhibitors represent a promising therapeutic strategy for overcoming PARP inhibitor resistance in patients with BRCA-mutant/HR-deficient tumors and support continued testing in clinical trials. Significance: KSQ-4279 is a potent and selective inhibitor of USP1 that induces regression of PARP inhibitor-resistant tumors when dosed in combination with PARP inhibitors, addressing an unmet clinical need for BRCA-mutant tumors.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11474170PMC
http://dx.doi.org/10.1158/0008-5472.CAN-24-0293DOI Listing

Publication Analysis

Top Keywords

parp inhibitor
12
parp inhibitors
12
tumors
9
usp1 inhibitor
8
inhibitor resistance
8
dna repair
8
brca-mutant tumors
8
unmet clinical
8
ksq-4279 potent
8
potent selective
8

Similar Publications

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!