CX-5461 activates the DNA damage response and demonstrates therapeutic efficacy in high-grade serous ovarian cancer

Sanij, E; Hannan, KM; Xuan, J; Yan, S; Ahern, JE; Trigos, AS; Brajanovski, N; Son, J; Chan, KT; Kondrashova, O; Lieschke, E; Wakefield, MJ; Frank, D; Ellis, S; Cullinane, C; Kang, J; Poortinga, G; Nag, P; Deans, AJ; Khanna, KK; Mileshkin, L; McArthur, GA; Soong, J; Berns, Emjj; Hannan, RD; Scott, CL; Sheppard, KE; Pearson, RB

Author(s): Sanij, E; Hannan, KM; Xuan, J; Yan, S; Ahern, JE; Trigos, AS; Brajanovski, N; Son, J; Chan, KT; Kondrashova, O; Lieschke, E; Wakefield, MJ; Frank, D; Ellis, S; Cullinane, C; Kang, J; Poortinga, G; Nag, P; Deans, AJ; Khanna, KK; Mileshkin, L; McArthur, GA; Soong, J; Berns, Emjj; Hannan, RD; Scott, CL; Sheppard, KE; Pearson, RB;
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
Research Division(s): Bioinformatics; Blood Cells And Blood Cancer; Cancer Biology And Stem Cells
PubMed ID: 32457376
Publisher's Version: https://doi.org/10.1038/s41467-020-16393-4
Open Access at Publisher's Site: https://doi.org/10.1038/s41467-020-16393-4
NHMRC Grants: NHMRC/1053792,
Terms of Use/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