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

• Published in: Nature communications Vol. 11; no. 1; pp. 2641 - 18
• Main Authors: Sanij, Elaine, Hannan, Katherine M, Xuan, Jiachen, Yan, Shunfei, Ahern, Jessica E, Trigos, Anna S, Brajanovski, Natalie, Son, Jinbae, Chan, Keefe T, Kondrashova, Olga, Lieschke, Elizabeth, Wakefield, Matthew J, Frank, Daniel, Ellis, Sarah, Cullinane, Carleen, Kang, Jian, Poortinga, Gretchen, Nag, Purba, Deans, Andrew J, Khanna, Kum Kum, Mileshkin, Linda, McArthur, Grant A, Soong, John, Berns, Els M J J, Hannan, Ross D, Scott, Clare L, Sheppard, Karen E, Pearson, Richard B
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 26.05.2020; Nature Publishing Group UK; Nature Portfolio
• Subjects: Animals; Benzothiazoles - pharmacology; Cancer; Cell Line, Tumor; Cystadenocarcinoma, Serous - drug therapy; Cystadenocarcinoma, Serous - genetics; Cystadenocarcinoma, Serous - metabolism; Damage; Deoxyribonucleic acid; Disease resistance; DNA; DNA Damage; DNA repair; DNA Replication - drug effects; DNA-directed RNA polymerase; Drug Resistance, Neoplasm; Enzyme Inhibitors - pharmacology; Female; Gene expression; Heterografts; Homologous Recombination; Homology; Humans; Inhibitors; Medical treatment; Mice; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Models, Biological; MRE11 protein; Naphthyridines - pharmacology; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Replication; Replication forks; Ribonucleic acid; RNA; RNA polymerase; RNA Polymerase I - antagonists & inhibitors; rRNA; Sensitivity; Transcription; Transcriptome; Xenografts; Xenotransplantation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-16393-4

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.