2. Academic Validation
  3. Distinct roles of treatment schemes and BRCA2 on the restoration of homologous recombination DNA repair and PARP inhibitor resistance in ovarian cancer

Distinct roles of treatment schemes and BRCA2 on the restoration of homologous recombination DNA repair and PARP inhibitor resistance in ovarian cancer

  • Oncogene. 2022 Oct 12. doi: 10.1038/s41388-022-02491-8.
Tzu-Ting Huang 1,  Sandra Sczerba Burkett 2,  Mayank Tandon 3,  Tomomi M Yamamoto 4,  Nitasha Gupta 1,  Benjamin G Bitler 4,  Jung-Min Lee # 5,  Jayakumar R Nair # 1
Affiliations

Affiliations

  • 1 Women's Malignancies Branch (WMB), Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA.
  • 2 Molecular Cytogenetic Core Facility, MCGP, CCR, NCI, NIH, Frederick, MD, USA.
  • 3 Center for Cancer Research Collaborative Bioinformatics Resource, CCR, NCI, NIH, Bethesda, MD, USA.
  • 4 Department of OB/GYN, Division of Reproductive Sciences, The University of Colorado, Aurora, CO, USA.
  • 5 Women's Malignancies Branch (WMB), Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA. leej6@mail.nih.gov.
  • # Contributed equally.
PMID: 36224341 DOI: 10.1038/s41388-022-02491-8
Abstract

Poly (ADP-ribose) polymerase inhibitors (PARPis) represent a major advance in ovarian Cancer, now as a treatment and as a maintenance therapy in the upfront and recurrent settings. However, patients often develop resistance to PARPis, underlining the importance of dissecting resistance mechanisms. Here, we report different dosing/timing schemes of PARPi treatment in BRCA2-mutant PEO1 cells, resulting in the simultaneous development of distinct resistance mechanisms. PARPi-resistant variants PEO1/OlaJR, established by higher initial doses and short-term PARPi treatment, develops PARPi resistance by rapidly restoring functional BRCA2 and promoting drug efflux activity. In contrast, PEO1/OlaR, developed by lower initial doses with long-term PARPi exposure, shows no regained BRCA2 function but a mesenchymal-like phenotype with greater invasion ability, and exhibits activated ATR/Chk1 and suppressed EZH2/MUS81 signaling cascades to regain HR repair and fork stabilization, respectively. Our study suggests that PARPi resistance mechanisms can be governed by treatment strategies and have a molecular basis on BRCA2 functionality. Further, we define different mechanisms that may serve as useful biomarkers to assess subsequent treatment strategies in PARPi-resistant ovarian Cancer.

Figures
Products
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