CX-5461 activates the DNA damage response and demonstrates therapeutic efficacy in high-grade serous ovarian cancer
Details
Publication Year 2020-05-26, Volume 11, Issue #1, Page 2641
Journal Title
Nature Communications
Publication Type
Journal Article
Abstract
Acquired resistance to PARP inhibitors (PARPi) is a major challenge for the clinical management of high grade serous ovarian cancer (HGSOC). Here, we demonstrate CX-5461, the first-in-class inhibitor of RNA polymerase I transcription of ribosomal RNA genes (rDNA), induces replication stress and activates the DNA damage response. CX-5461 co-operates with PARPi in exacerbating replication stress and enhances therapeutic efficacy against homologous recombination (HR) DNA repair-deficient HGSOC-patient-derived xenograft (PDX) in vivo. We demonstrate CX-5461 has a different sensitivity spectrum to PARPi involving MRE11-dependent degradation of replication forks. Importantly, CX-5461 exhibits in vivo single agent efficacy in a HGSOC-PDX with reduced sensitivity to PARPi by overcoming replication fork protection. Further, we identify CX-5461-sensitivity gene expression signatures in primary and relapsed HGSOC. We propose CX-5461 is a promising therapy in combination with PARPi in HR-deficient HGSOC and also as a single agent for the treatment of relapsed disease.
Publisher
NPG
WEHI Research Division(s)
Bioinformatics; Blood Cells And Blood Cancer; Cancer Biology And Stem Cells
PubMed ID
32457376
Open Access at Publisher's Site
https://doi.org/10.1038/s41467-020-16393-4
NHMRC Grants
NHMRC/1053792
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2020-06-03 09:37:47
Last Modified: 2020-06-03 09:52:28
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