Highlights
- •Primary PARPi resistance could not be explained completely by mutations in BRCA1/2 or HRD related genes.
- •Multiple and heterogeneous processes could be involved in the development of PARPi resistance
- •The acquired resistance by long-term treatment selection had evolutional dynamics to tolerate the stress of PARPi.
- •Long-term PARPi treatment could induce accumulating de nove SNVs.
- •Depressed EP300 could cause resistant phenotype through activated epithelial-mesenchymal transition process.
Abstract
Background
Patients with epithelial ovarian cancer (EOC) can benefit from poly- (ADP ribose)
polymerase inhibitors (PARPi) therapy. However, PARPi resistance has become a challenge
in clinical practice, and its mechanism requires further exploration.
Methods
We established three PARPi-resistant cell strains following olaparib exposure. CCK-8,
clonogenic survival, transwell, wound healing, cell cycle, RT-qPCR and western blot
assays were performed to explore the functional phenotype of the resistant cells.
Whole-exome sequencing and RNA-sequencing were performed to identify the altered genes.
Stable knockdown and overexpression were used to investigate the role of EP300, an
upstream regulator of E-cadherin and epithelial-mesenchymal transition (EMT), in cell
lines. We further validated the finding in clinical ovarian cancer samples by immunohistochemistry.
Results
We combined public datasets to obtain an integrated PARPi sensitivity profile in EOC
cells, which indicated that primary PARPi resistance could not be fully explained
by mutations in BRCA1/2 or homologous recombination deficiency related genes. Genomic
and transcriptome analyses revealed distinct mechanisms between primary and acquired
resistance. Long-term PARPi treatment induced accumulation of de novo single nucleotide
variants (SNV), and the complete frame-shift deletion of PARP1 was detected in the A2780 resistant strain. Additionally, the depressed histone acetyltransferase
of EP300 could cause resistant phenotype through activated EMT process in vitro, and
associated with PARPi-resistance in EOC patients.
Conclusion
Long-term PARPi treatment led to evolutionary genomic and transcriptional alterations
that were associated with acquired resistance, among which depressed EP300 partly
contributed to the resistant phenotype.
Keywords
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Article info
Publication history
Published online: October 18, 2022
Accepted:
October 10,
2022
Received in revised form:
October 6,
2022
Received:
May 3,
2022
Identification
Copyright
© 2022 Published by Elsevier Inc.
