scholarly journals Inhibition of RNA Polymerase I Transcription Activates Targeted DNA Damage Response and Enhances the Efficacy of PARP Inhibitors in High-Grade Serous Ovarian Cancer

2019 ◽  
Author(s):  
Elaine Sanij ◽  
Katherine M. Hannan ◽  
Shunfei Yan ◽  
Jiachen Xuan ◽  
Jessica E. Ahern ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Parp Inhibitors ◽  
Rna Polymerase I ◽  
High Grade ◽  
Replication Forks ◽  
Serous Ovarian Cancer ◽  
Damage Response ◽  
Polymerase I

AbstractHigh-grade serous ovarian cancer (HGSOC) accounts for the majority of ovarian cancer and has a dismal prognosis. PARP inhibitors (PARPi) have revolutionized disease management of patients with homologous recombination (HR) DNA repair-deficient HGSOC. However, acquired resistance to PARPi by complex mechanisms including HR restoration and stabilisation of replication forks is a major challenge in the clinic. Here, we demonstrate CX-5461, an inhibitor of RNA polymerase I transcription of ribosomal RNA genes (rDNA), induces replication stress at rDNA leading to activation of DNA damage response and DNA damage involving MRE11-dependent degradation of replication forks. CX-5461 cooperates with PARPi in exacerbating DNA damage and enhances synthetic lethal interactions of PARPi with HR deficiency in HGSOC-patient-derived xenograft (PDX)in vivo. We demonstrate CX-5461 has a different sensitivity spectrum to PARPi and destabilises replication forks irrespective of HR pathway status, overcoming two well-known mechanisms of resistance to PARPi. Importantly, CX-5461 exhibits single agent efficacy in PARPi-resistant HGSOC-PDX. Further, we identify CX-5461-sensitivity gene expression signatures in primary and relapsed HGSOC. Therefore, CX-5461 is a promising therapy alone and in combination therapy with PARPi in HR-deficient HGSOC. CX-5461 is also an exciting treatment option for patients with relapsed HGSOC tumors that have poor clinical outcome.

scholarly journals Targeting RNA Polymerase I transcription synergises with TOP1 inhibition in potentiating the DNA damage response in high-grade serous ovarian cancer

2019 ◽  
Author(s):  
Shunfei Yan ◽  
Piyush B. Madhamshettiwar ◽  
Kaylene J. Simpson ◽  
Sarah Ellis ◽  
Jian Kang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Rna Polymerase ◽  
Dna Damage Response ◽  
Parp Inhibitor ◽  
Rna Polymerase I ◽  
Serous Carcinoma ◽  
High Grade ◽  
Damage Response ◽  
Polymerase I

AbstractLimited effective therapeutic options are available for patients with recurrent high-grade serous carcinoma (HGSC), the most common histological subtype accounting for the majority of ovarian cancer deaths. We have shown efficacy in poly-ADP ribose polymerase (PARP) inhibitor-resistant HGSC for the RNA Polymerase I (Pol I) transcription inhibitor CX-5461 through its ability to activate a nucleolar-associated DNA damage response (DDR). Here, we screen the protein-coding genome to identify potential targets whose inhibition enhances the efficacy of CX-5461. We identify a network of cooperating inhibitory interactions, including components of homologous recombination (HR) DNA repair and DNA topoisomerase 1 (TOP1). We highlight that CX-5461 combined with topotecan, a TOP1 inhibitor used as salvage therapy in HGSC, induces robust cell cycle arrest and cell death in a panel of HR-proficient HGSC cell lines. The combination potentiates a nucleolar-associated DDR via recruitment of phosphorylated replication protein A (RPA) and ataxia telangiectasia and Rad3 related protein (ATR). CX-5461 plus low-dose topotecan cooperate to potently inhibit xenograft tumour growth, indicating the potential for this strategy to improve salvage therapeutic regimens to treat HGSC.

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

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Elaine Sanij ◽  
Katherine M. Hannan ◽  
Jiachen Xuan ◽  
Shunfei Yan ◽  
Jessica E. Ahern ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Therapeutic Efficacy ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Damage Response

scholarly journals The RNA polymerase I transcription inhibitor CX-5461 cooperates with topoisomerase 1 inhibition by enhancing the DNA damage response in homologous recombination-proficient high-grade serous ovarian cancer

2020 ◽  
Author(s):  
Shunfei Yan ◽  
Jiachen Xuan ◽  
Natalie Brajanovski ◽  
Madeleine R. C. Tancock ◽  
Piyush B. Madhamshettiwar ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Homologous Recombination ◽  
Dna Damage Response ◽  
Cell Cycle Checkpoint ◽  
Common Mechanism ◽  
High Grade ◽  
M Cell ◽  
Topoisomerase 1 ◽  
Damage Response

Abstract Background 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. Methods Herein, we screen the whole protein-coding genome to identify potential targets whose depletion cooperates with CX-5461 in HR-proficient HGSC. Results 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. Conclusions 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.

scholarly journals DNA intercalator BMH-21 inhibits RNA polymerase I independent of DNA damage response

Oncotarget ◽  
2014 ◽  
Vol 5 (12) ◽  
pp. 4361-4369 ◽  
Author(s):  
Laureen Colis ◽  
Karita Peltonen ◽  
Paul Sirajuddin ◽  
Hester Liu ◽  
Sara Sanders ◽  
...  
Keyword(s):  
Dna Damage ◽  
Rna Polymerase ◽  
Dna Damage Response ◽  
Rna Polymerase I ◽  
Dna Intercalator ◽  
Damage Response ◽  
Polymerase I

scholarly journals Association between DNA Damage Response and Repair Genes and Risk of Invasive Serous Ovarian Cancer

PLoS ONE ◽  
2010 ◽  
Vol 5 (4) ◽  
pp. e10061 ◽  
Author(s):  
Joellen M. Schildkraut ◽  
Edwin S. Iversen ◽  
Melanie A. Wilson ◽  
Merlise A. Clyde ◽  
Patricia G. Moorman ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Serous Ovarian Cancer ◽  
Damage Response ◽  
Repair Genes

scholarly journals Genomic, Transcriptomic, and Functional Alterations in DNA Damage Response Pathways as Putative Biomarkers of Chemotherapy Response in Ovarian Cancer

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1420
Author(s):  
Sweta Sharma Saha ◽  
Lucy Gentles ◽  
Alice Bradbury ◽  
Dominik Brecht ◽  
Rebecca Robinson ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Personalised Medicine ◽  
Primary Cultures ◽  
The Cancer Genome Atlas ◽  
Chemotherapy Response ◽  
Chemotherapy Drugs ◽  
Ovarian Cancers ◽  
Damage Response

Defective DNA damage response (DDR) pathways are enabling characteristics of cancers that not only can be exploited to specifically target cancer cells but also can predict chemotherapy response. Defective Homologous Recombination Repair (HRR) function, e.g., due to BRCA1/2 loss, is a determinant of response to platinum agents and PARP inhibitors in ovarian cancers. Most chemotherapies function by either inducing DNA damage or impacting on its repair but are generally used in the clinic unselectively. The significance of HRR and other DDR pathways in determining response to several other chemotherapy drugs is not well understood. In this study, the genomic, transcriptomic and functional analysis of DDR pathways in a panel of 14 ovarian cancer cell lines identified that defects in DDR pathways could determine response to several chemotherapy drugs. Carboplatin, rucaparib, and topotecan sensitivity were associated with functional loss of HRR (validated in 10 patient-derived primary cultures) and mismatch repair. Two DDR gene expression clusters correlating with treatment response were identified, with PARP10 identified as a novel marker of platinum response, which was confirmed in The Cancer Genome Atlas (TCGA) ovarian cancer cohort. Reduced non-homologous end-joining function correlated with increased sensitivity to doxorubicin, while cells with high intrinsic oxidative stress showed sensitivity to gemcitabine. In this era of personalised medicine, molecular/functional characterisation of DDR pathways could guide chemotherapy choices in the clinic allowing specific targeting of ovarian cancers.

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