2. Academic Validation
  3. BRCA2 reversion mutation-independent resistance to PARP inhibition through impaired DNA prereplication complex function

BRCA2 reversion mutation-independent resistance to PARP inhibition through impaired DNA prereplication complex function

  • Proc Natl Acad Sci U S A. 2025 Jun 10;122(23):e2426743122. doi: 10.1073/pnas.2426743122.
Kyrie Pappas 1,  Matteo Ferrari 2,  Perianne Smith 3,  Subhiksha Nandakumar 4 5,  Zahra Khan 1,  Serina B Young 6,  Justin LaClair 7,  Marco Vincenzo Russo 8,  Emmet Huang-Hobbs 1,  Nikolaus Schultz 1 4 5,  Wassim Abida 9,  Wouter Karthaus 10,  Maria Jasin 2,  Charles L Sawyers 1 11
Affiliations

Affiliations

  • 1 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
  • 2 Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
  • 3 Department of Microbiology, Immunology, and Cancer Biology, University of Minnesota, Minneapolis, MN 55455.
  • 4 Computational Oncology Service, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
  • 5 The Halvorsen Center for Computational Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
  • 6 Department of Neurosurgery, Columbia University Irving Medical Center, New York, NY 10032.
  • 7 Albany Medical College, Albany, NY 12208.
  • 8 Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136.
  • 9 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
  • 10 Swiss Institute for Experimental Cancer Research, The École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland 1015.
  • 11 HHMI, Chevy Chase, MD 20815.
PMID: 40460119 DOI: 10.1073/pnas.2426743122
Abstract

Recent approvals of polymeric adenosine diphosphate ribose (poly(ADP-ribose) polymerase inhibitors (PARPi) for BRCA-mutant metastatic castration resistant prostate Cancer necessitate an understanding of the factors that shape sensitivity and resistance. Reversion mutations that restore homologous recombination (HR) repair are detected in ~50 to 80% of BRCA-mutant patients who respond but subsequently relapse, but there is currently little insight into why only ~50% of BRCA-mutant patients display upfront resistance. To address this question, we performed a genome-wide CRISPR screen to identify genomic determinants of PARPi resistance in murine Brca2Δ/Δ prostate organoids genetically engineered in a manner that precludes the development of reversion mutations. Remarkably, we recovered multiple independent single guide RNAs (sgRNAs) targeting three different members (Cdt1, Cdc6, and Dbf4) of the DNA prereplication complex (pre-RC), each of which independently conferred resistance to olaparib and the next-generation PARP-1 selective inhibitor AZD5305. Moreover, sensitivity to PARP inhibition was restored in Brca2Δ/Δ, Cdc6-depleted prostate cells by knockdown of geminin, a negative regulator of Cdt1, further implicating the critical role of a functional pre-RC complex in PARPi sensitivity. Furthermore, ~50% of CRPC tumors have copy number loss of pre-RC complex genes, particularly CDT1. Mechanistically, prostate cells with impaired pre-RC activity displayed rapid resolution of olaparib-induced DNA damage as well as protection from replication fork degradation caused by Brca2 loss, providing insight into how Brca2-mutant Cancer cells can escape cell death from replication stress induced by PARP inhibition in the absence of HR repair. Of note, a pharmacologic inhibitor that targets the CDT1/geminin complex (AF615) restored sensitivity to AZD5305, providing a potential translational avenue to enhance sensitivity to PARP inhibition.

Keywords

CDT1; PARP; geminin; homologous recombination; prostate.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-132167
    99.76%, PARP抑制剂
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z