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CX-5461 Treatment Leads to Cytosolic DNA-Mediated STING Activation in Ovarian Cancer

SIMPLE SUMMARY: CX-5461 is an RNA polymerase I inhibitor that is in clinical trials for both advanced hematological cancers and solid tumors. Experimentally, this drug has been shown to induce a p53-independent DNA damage response through ATM and ATR kinase, and has particular activity against chemo...

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Autores principales: Cornelison, Robert, Biswas, Kuntal, Llaneza, Danielle C., Harris, Alexandra R., Sosale, Nisha G., Lazzara, Matthew J., Landen, Charles N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8533980/
https://www.ncbi.nlm.nih.gov/pubmed/34680204
http://dx.doi.org/10.3390/cancers13205056
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author Cornelison, Robert
Biswas, Kuntal
Llaneza, Danielle C.
Harris, Alexandra R.
Sosale, Nisha G.
Lazzara, Matthew J.
Landen, Charles N.
author_facet Cornelison, Robert
Biswas, Kuntal
Llaneza, Danielle C.
Harris, Alexandra R.
Sosale, Nisha G.
Lazzara, Matthew J.
Landen, Charles N.
author_sort Cornelison, Robert
collection PubMed
description SIMPLE SUMMARY: CX-5461 is an RNA polymerase I inhibitor that is in clinical trials for both advanced hematological cancers and solid tumors. Experimentally, this drug has been shown to induce a p53-independent DNA damage response through ATM and ATR kinase, and has particular activity against chemoresistant tumors. The current study shows for the first time that CX-5461 treatment in ovarian cancer cells induces the release of cytoplasmic DNA that stimulates cGAS–STING signaling, leading to the production of IFN type I in both cancer cells and xenografts in vivo. Because the cGAS–STING pathway is a key mediator of the immune response against cancer cells, this novel finding may lead to utilization of RNA Pol I inhibitors in combination with checkpoint inhibition. ABSTRACT: Epithelial ovarian cancer (EOC) is the deadliest of the gynecologic malignancies, with an overall survival rate of <30%. Recent research has suggested that targeting RNA polymerase I (POL I) with small-molecule inhibitors may be a viable therapeutic approach to combating EOC, even when chemoresistance is present. CX-5461 is one of the most promising POL I inhibitors currently being investigated, and previous reports have shown that CX-5461 treatment induces DNA damage response (DDR) through ATM/ATR kinase. Investigation into downstream effects of CX-5461 led us to uncovering a previously unreported phenotype. Treatment with CX-5461 induces a rapid accumulation of cytosolic DNA. This accumulation leads to transcriptional upregulation of ‘STimulator of Interferon Genes’ (STING) in the same time frame, phosphorylation of IRF3, and activation of type I interferon response both in vitro and in vivo. This activation is mediated and dependent on cyclic GMP–AMP synthase (cGAS). Here, we show THAT CX-5461 leads to an accumulation of cytosolic dsDNA and thereby activates the cGAS–STING–TBK1–IRF3 innate immune pathway, which induces type I IFN. CX-5461 treatment-mediated immune activation may be a powerful mechanism of action to exploit, leading to novel drug combinations with a chance of increasing immunotherapy efficacy, possibly with some cancer specificity limiting deleterious toxicities.
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spelling pubmed-85339802021-10-23 CX-5461 Treatment Leads to Cytosolic DNA-Mediated STING Activation in Ovarian Cancer Cornelison, Robert Biswas, Kuntal Llaneza, Danielle C. Harris, Alexandra R. Sosale, Nisha G. Lazzara, Matthew J. Landen, Charles N. Cancers (Basel) Article SIMPLE SUMMARY: CX-5461 is an RNA polymerase I inhibitor that is in clinical trials for both advanced hematological cancers and solid tumors. Experimentally, this drug has been shown to induce a p53-independent DNA damage response through ATM and ATR kinase, and has particular activity against chemoresistant tumors. The current study shows for the first time that CX-5461 treatment in ovarian cancer cells induces the release of cytoplasmic DNA that stimulates cGAS–STING signaling, leading to the production of IFN type I in both cancer cells and xenografts in vivo. Because the cGAS–STING pathway is a key mediator of the immune response against cancer cells, this novel finding may lead to utilization of RNA Pol I inhibitors in combination with checkpoint inhibition. ABSTRACT: Epithelial ovarian cancer (EOC) is the deadliest of the gynecologic malignancies, with an overall survival rate of <30%. Recent research has suggested that targeting RNA polymerase I (POL I) with small-molecule inhibitors may be a viable therapeutic approach to combating EOC, even when chemoresistance is present. CX-5461 is one of the most promising POL I inhibitors currently being investigated, and previous reports have shown that CX-5461 treatment induces DNA damage response (DDR) through ATM/ATR kinase. Investigation into downstream effects of CX-5461 led us to uncovering a previously unreported phenotype. Treatment with CX-5461 induces a rapid accumulation of cytosolic DNA. This accumulation leads to transcriptional upregulation of ‘STimulator of Interferon Genes’ (STING) in the same time frame, phosphorylation of IRF3, and activation of type I interferon response both in vitro and in vivo. This activation is mediated and dependent on cyclic GMP–AMP synthase (cGAS). Here, we show THAT CX-5461 leads to an accumulation of cytosolic dsDNA and thereby activates the cGAS–STING–TBK1–IRF3 innate immune pathway, which induces type I IFN. CX-5461 treatment-mediated immune activation may be a powerful mechanism of action to exploit, leading to novel drug combinations with a chance of increasing immunotherapy efficacy, possibly with some cancer specificity limiting deleterious toxicities. MDPI 2021-10-09 /pmc/articles/PMC8533980/ /pubmed/34680204 http://dx.doi.org/10.3390/cancers13205056 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Cornelison, Robert
Biswas, Kuntal
Llaneza, Danielle C.
Harris, Alexandra R.
Sosale, Nisha G.
Lazzara, Matthew J.
Landen, Charles N.
CX-5461 Treatment Leads to Cytosolic DNA-Mediated STING Activation in Ovarian Cancer
title CX-5461 Treatment Leads to Cytosolic DNA-Mediated STING Activation in Ovarian Cancer
title_full CX-5461 Treatment Leads to Cytosolic DNA-Mediated STING Activation in Ovarian Cancer
title_fullStr CX-5461 Treatment Leads to Cytosolic DNA-Mediated STING Activation in Ovarian Cancer
title_full_unstemmed CX-5461 Treatment Leads to Cytosolic DNA-Mediated STING Activation in Ovarian Cancer
title_short CX-5461 Treatment Leads to Cytosolic DNA-Mediated STING Activation in Ovarian Cancer
title_sort cx-5461 treatment leads to cytosolic dna-mediated sting activation in ovarian cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8533980/
https://www.ncbi.nlm.nih.gov/pubmed/34680204
http://dx.doi.org/10.3390/cancers13205056
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