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Targeting RNA-Polymerase I in Both Chemosensitive and Chemoresistant Populations in Epithelial Ovarian Cancer.
Clin Cancer Res. 2017 Nov 01; 23(21):6529-6540.CC

Abstract

Purpose:

A hallmark of neoplasia is increased ribosome biogenesis, and targeting this process with RNA polymerase I (Pol I) inhibitors has shown some efficacy. We examined the contribution and potential targeting of ribosomal machinery in chemotherapy-resistant and -sensitive models of ovarian cancer.

Experimental Design:

Pol I machinery expression was examined, and subsequently targeted with the Pol I inhibitor CX-5461, in ovarian cancer cell lines, an immortalized surface epithelial line, and patient-derived xenograft (PDX) models with and without chemotherapy. Effects on viability, Pol I occupancy of rDNA, ribosomal content, and chemosensitivity were examined.

Results:

In PDX models, ribosomal machinery components were increased in chemotherapy-treated tumors compared with controls. Thirteen cell lines were sensitive to CX-5461, with IC50s 25 nmol/L-2 μmol/L. Interestingly, two chemoresistant lines were 10.5- and 5.5-fold more sensitive than parental lines. CX-5461 induced DNA damage checkpoint activation and G2-M arrest with increased γH2AX staining. Chemoresistant cells had 2- to 4-fold increased rDNA Pol I occupancy and increased rRNA synthesis, despite having slower proliferation rates, whereas ribosome abundance and translational efficiency were not impaired. In five PDX models treated with CX-5461, one showed a complete response, one a 55% reduction in tumor volume, and one maintained stable disease for 45 days.

Conclusions:

Pol I inhibition with CX-5461 shows high activity in ovarian cancer cell lines and PDX models, with an enhanced effect on chemoresistant cells. Effects occur independent of proliferation rates or dormancy. This represents a novel therapeutic approach that may have preferential activity in chemoresistant populations. Clin Cancer Res; 23(21); 6529-40. ©2017 AACR.

Authors+Show Affiliations

Department of Obstetrics and Gynecology, University of Virginia, Charlottesville, Virginia.Department of Obstetrics and Gynecology, University of Chicago, Chicago, Illinois.Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama.Department of Obstetrics and Gynecology, Busan Paik Hospital, Busan, Korea.Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, Alabama.Department of Medicine, Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, Alabama.Department of Obstetrics and Gynecology, University of Virginia, Charlottesville, Virginia.Department of Obstetrics and Gynecology, University of Virginia, Charlottesville, Virginia.Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama.Department of Obstetrics and Gynecology, University of Virginia, Charlottesville, Virginia.Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, Alabama.Department of Obstetrics and Gynecology, University of Virginia, Charlottesville, Virginia. clanden@virginia.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28778862

Citation

Cornelison, Robert, et al. "Targeting RNA-Polymerase I in Both Chemosensitive and Chemoresistant Populations in Epithelial Ovarian Cancer." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, vol. 23, no. 21, 2017, pp. 6529-6540.
Cornelison R, Dobbin ZC, Katre AA, et al. Targeting RNA-Polymerase I in Both Chemosensitive and Chemoresistant Populations in Epithelial Ovarian Cancer. Clin Cancer Res. 2017;23(21):6529-6540.
Cornelison, R., Dobbin, Z. C., Katre, A. A., Jeong, D. H., Zhang, Y., Chen, D., Petrova, Y., Llaneza, D. C., Steg, A. D., Parsons, L., Schneider, D. A., & Landen, C. N. (2017). Targeting RNA-Polymerase I in Both Chemosensitive and Chemoresistant Populations in Epithelial Ovarian Cancer. Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 23(21), 6529-6540. https://doi.org/10.1158/1078-0432.CCR-17-0282
Cornelison R, et al. Targeting RNA-Polymerase I in Both Chemosensitive and Chemoresistant Populations in Epithelial Ovarian Cancer. Clin Cancer Res. 2017 Nov 1;23(21):6529-6540. PubMed PMID: 28778862.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Targeting RNA-Polymerase I in Both Chemosensitive and Chemoresistant Populations in Epithelial Ovarian Cancer. AU - Cornelison,Robert, AU - Dobbin,Zachary C, AU - Katre,Ashwini A, AU - Jeong,Dae Hoon, AU - Zhang,Yinfeng, AU - Chen,Dongquan, AU - Petrova,Yuliya, AU - Llaneza,Danielle C, AU - Steg,Adam D, AU - Parsons,Laura, AU - Schneider,David A, AU - Landen,Charles N, Y1 - 2017/08/04/ PY - 2017/01/30/received PY - 2017/05/25/revised PY - 2017/07/25/accepted PY - 2017/8/6/pubmed PY - 2018/7/24/medline PY - 2017/8/6/entrez SP - 6529 EP - 6540 JF - Clinical cancer research : an official journal of the American Association for Cancer Research JO - Clin. Cancer Res. VL - 23 IS - 21 N2 - Purpose: A hallmark of neoplasia is increased ribosome biogenesis, and targeting this process with RNA polymerase I (Pol I) inhibitors has shown some efficacy. We examined the contribution and potential targeting of ribosomal machinery in chemotherapy-resistant and -sensitive models of ovarian cancer.Experimental Design: Pol I machinery expression was examined, and subsequently targeted with the Pol I inhibitor CX-5461, in ovarian cancer cell lines, an immortalized surface epithelial line, and patient-derived xenograft (PDX) models with and without chemotherapy. Effects on viability, Pol I occupancy of rDNA, ribosomal content, and chemosensitivity were examined.Results: In PDX models, ribosomal machinery components were increased in chemotherapy-treated tumors compared with controls. Thirteen cell lines were sensitive to CX-5461, with IC50s 25 nmol/L-2 μmol/L. Interestingly, two chemoresistant lines were 10.5- and 5.5-fold more sensitive than parental lines. CX-5461 induced DNA damage checkpoint activation and G2-M arrest with increased γH2AX staining. Chemoresistant cells had 2- to 4-fold increased rDNA Pol I occupancy and increased rRNA synthesis, despite having slower proliferation rates, whereas ribosome abundance and translational efficiency were not impaired. In five PDX models treated with CX-5461, one showed a complete response, one a 55% reduction in tumor volume, and one maintained stable disease for 45 days.Conclusions: Pol I inhibition with CX-5461 shows high activity in ovarian cancer cell lines and PDX models, with an enhanced effect on chemoresistant cells. Effects occur independent of proliferation rates or dormancy. This represents a novel therapeutic approach that may have preferential activity in chemoresistant populations. Clin Cancer Res; 23(21); 6529-40. ©2017 AACR. SN - 1078-0432 UR - https://www.unboundmedicine.com/medline/citation/28778862/Targeting_RNA_Polymerase_I_in_Both_Chemosensitive_and_Chemoresistant_Populations_in_Epithelial_Ovarian_Cancer_ L2 - http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=28778862 DB - PRIME DP - Unbound Medicine ER -