Gene expression-based discovery of atovaquone as a STAT3 inhibitor and anticancer agent.

The oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3) is frequently activated inappropriately in a wide range of hematological and solid cancers, but clinically available therapies targeting STAT3 are lacking. Using a computational strategy to identify compounds opposing the gene expression signature of STAT3, we discovered atovaquone (Mepron), an antimicrobial approved by the US Food and Drug Administration, to be a potent STAT3 inhibitor. We show that, at drug concentrations routinely achieved clinically in human plasma, atovaquone inhibits STAT3 phosphorylation, the expression of STAT3 target genes, and the viability of STAT3-dependent hematological cancer cells. These effects were also observed with atovaquone treatment of primary blasts isolated from patients with acute myelogenous leukemia or acute lymphocytic leukemia. Atovaquone is not a kinase inhibitor but instead rapidly and specifically downregulates cell-surface expression of glycoprotein 130, which is required for STAT3 activation in multiple contexts. The administration of oral atovaquone to mice inhibited tumor growth and prolonged survival in a murine model of multiple myeloma. Finally, in patients with acute myelogenous leukemia treated with hematopoietic stem cell transplantation, extended use of atovaquone for Pneumocystis prophylaxis was associated with improved relapse-free survival. These findings establish atovaquone as a novel, clinically accessible STAT3 inhibitor with evidence of anticancer efficacy in both animal models and humans. © 2016 by The American Society of Hematology.

Citation

Michael Xiang, Haesook Kim, Vincent T Ho, Sarah R Walker, Michal Bar-Natan, Melodi Anahtar, Suhu Liu, Patricia A Toniolo, Yasmin Kroll, Nichole Jones, Zachary T Giaccone, Lisa N Heppler, Darwin Q Ye, Jason J Marineau, Daniel Shaw, James E Bradner, Traci Blonquist, Donna Neuberg, Claudio Hetz, Richard M Stone, Robert J Soiffer, David A Frank. Gene expression-based discovery of atovaquone as a STAT3 inhibitor and anticancer agent. Blood. 2016 Oct 06;128(14):1845-1853

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PMID: 27531676

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