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The dual inhibition of RNA Pol I transcription and PIM kinase as a new therapeutic approach to treat advanced prostate cancer

Rebello, Richard J, Kusnadi, Eric, Cameron, Donald P, Pearson, Helen, Lesmana, Analia, Devlin, Jennifer R., Drygin, Denis, Clark, Ashlee K., Porter, Laura, Pedersen, John, Sandhu, Shahneen, Risbridger, Gail P., Pearson, Richard B., Hannan, Ross D. and Furic, Luc 2016. The dual inhibition of RNA Pol I transcription and PIM kinase as a new therapeutic approach to treat advanced prostate cancer. Clinical Cancer Research 22 (22) , pp. 5539-5552. 10.1158/1078-0432.CCR-16-0124

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Abstract

Purpose: The MYC oncogene is frequently overexpressed in prostate cancer. Upregulation of ribosome biogenesis and function is characteristic of MYC-driven tumors. In addition, PIM kinases activate MYC signaling and mRNA translation in prostate cancer and cooperate with MYC to accelerate tumorigenesis. Here, we investigate the efficacy of a single and dual approach targeting ribosome biogenesis and function to treat prostate cancer. Experimental Design: The inhibition of ribosomal RNA (rRNA) synthesis with CX-5461, a potent, selective, and orally bioavailable inhibitor of RNA polymerase I (Pol I) transcription, has been successfully exploited therapeutically but only in models of hematologic malignancy. CX-5461 and CX-6258, a pan-PIM kinase inhibitor, were tested alone and in combination in prostate cancer cell lines, in Hi-MYC- and PTEN-deficient mouse models and in patient-derived xenografts (PDX) of metastatic tissue obtained from a patient with castration-resistant prostate cancer. Results: CX-5461 inhibited anchorage-independent growth and induced cell-cycle arrest in prostate cancer cell lines at nanomolar concentrations. Oral administration of 50 mg/kg CX-5461 induced TP53 expression and activity and reduced proliferation (MKI67) and invasion (loss of ductal actin) in Hi-MYC tumors, but not in PTEN-null (low MYC) tumors. While 100 mg/kg CX-6258 showed limited effect alone, its combination with CX-5461 further suppressed proliferation and dramatically reduced large invasive lesions in both models. This rational combination strategy significantly inhibited proliferation and induced cell death in PDX of prostate cancer. Conclusions: Our results demonstrate preclinical efficacy of targeting the ribosome at multiple levels and provide a new approach for the treatment of prostate cancer

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Publisher: American Association for Cancer Research
ISSN: 1078-0432
Date of First Compliant Deposit: 23 October 2017
Date of Acceptance: 21 July 2016
Last Modified: 03 Apr 2019 11:24
URI: http://orca-mwe.cf.ac.uk/id/eprint/105803

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