cx-5461 and Cystadenocarcinoma--Serous

Topics: Benzothiazoles; Cystadenocarcinoma, Serous; Female; Humans; Models, Genetic; Molecular Targeted Therapy; Naphthyridines; Ovarian Neoplasms; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors; RNA, Ribosomal

Intrinsic and acquired drug resistance represent fundamental barriers to the cure of high-grade serous ovarian carcinoma (HGSC), the most common histological subtype accounting for the majority of ovarian cancer deaths. Defects in homologous recombination (HR) DNA repair are key determinants of sensitivity to chemotherapy and poly-ADP ribose polymerase inhibitors. Restoration of HR is a common mechanism of acquired resistance that results in patient mortality, highlighting the need to identify new therapies targeting HR-proficient disease. We have shown promise for CX-5461, a cancer therapeutic in early phase clinical trials, in treating HR-deficient HGSC.. Herein, we screen the whole protein-coding genome to identify potential targets whose depletion cooperates with CX-5461 in HR-proficient HGSC.. We demonstrate robust proliferation inhibition in cells depleted of DNA topoisomerase 1 (TOP1). Combining the clinically used TOP1 inhibitor topotecan with CX-5461 potentiates a G2/M cell cycle checkpoint arrest in multiple HR-proficient HGSC cell lines. The combination enhances a nucleolar DNA damage response and global replication stress without increasing DNA strand breakage, significantly reducing clonogenic survival and tumour growth in vivo.. Our findings highlight the possibility of exploiting TOP1 inhibition to be combined with CX-5461 as a non-genotoxic approach in targeting HR-proficient HGSC.

Topics: Animals; Benzothiazoles; Cell Line, Tumor; Cell Proliferation; Cystadenocarcinoma, Serous; DNA Damage; DNA Replication; Drug Resistance, Neoplasm; Drug Synergism; Drug Therapy, Combination; Female; G1 Phase Cell Cycle Checkpoints; Genes, BRCA2; Homologous Recombination; Humans; M Phase Cell Cycle Checkpoints; Mice; Mice, Inbred NOD; Mice, SCID; Naphthyridines; Neoplasm Grading; Ovarian Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; RNA Interference; RNA Polymerase I; Topoisomerase I Inhibitors; Topotecan

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.

Topics: Animals; Benzothiazoles; Cell Line, Tumor; Cystadenocarcinoma, Serous; DNA Damage; DNA Replication; Drug Resistance, Neoplasm; Enzyme Inhibitors; Female; Heterografts; Homologous Recombination; Humans; Mice; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Models, Biological; Naphthyridines; Ovarian Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; RNA Polymerase I; Transcriptome