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

Cancers

卷:13

Nisha G. Sosale¹  Matthew J. Lazzara¹  Kuntal Biswas²  Charles N. Landen²  Danielle C. Llaneza²  Alexandra R. Harris²  Robert Cornelison² 

[1] Department of Chemical Engineering, University of Virginia, Charlottesville, VA 22908, USA;

[2] Department of Obstetrics and Gynecology, University of Virginia, Charlottesville, VA 22908, USA;

关键词: ovarian cancer;    ribosomal synthesis;    RNA polymerase I;    CX-5461;    chemoresistance;    patient-derived xenograft;   

DOI  :  10.3390/cancers13205056

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown