The STAT3 pathway is frequently overactive in non–small cell lung cancer (NSCLC), an often fatal disease with known risk factors including tobacco and chemical exposures. Whether STAT3 can be downmodulated to delay or prevent development of lung cancer resulting from an environmental exposure has not been previously tested. A circular oligonucleotide STAT3 decoy (CS3D) was used to treat mice previously exposed to the tobacco carcinogen nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. CS3D contains a double-stranded STAT3 DNA response element sequence and interrupts STAT3 signaling by binding to STAT3 dimers, rendering them unable to initiate transcription at native STAT3 DNA binding sites. An intermittent course of CS3D decreased the development of airway preneoplasias by 42% at 1 week posttreatment, reduced the progression of preneoplasia to adenomas by 54% at 8 weeks posttreatment, and reduced the size and number of resulting lung tumors by 49.7% and 29.5%, respectively, at 20 weeks posttreatment. No toxicity was detected. A mutant cyclic oligonucleotide with no STAT3 binding ability was used as a control. Chemopreventive effects were independent of the KRAS mutational status of the tumors. In lungs harvested during and after the treatment course with CS3D, airway preneoplasias had reduced STAT3 signaling. Chemopreventive effects were accompanied by decreased VEGFA expression, ablated IL6, COX-2, and p-NF-kB, and decreased pulmonary M2 macrophages and myeloid-derived suppressor cells. Thus, downmodulation of STAT3 activity using a decoy molecule both reduced oncogenic signaling in the airway epithelium and favored a lung microenvironment with reduced immunosuppression.
Bibliographical noteFunding Information:
This research was funded in part by a philanthropic gift from the 5th District Eagles of Minnesota to the Masonic Cancer Center. C. Njatcha was supported by a NCI fellowship from a T32 Cancer Biology Training Grant (T32 CA009138) and by an individual NCI fellowship (F31 CA213982). A. Almotlak was awarded a scholarship for graduate studies from the Cultural Mission to the United States (SACM). JMS was supported by the Frederick & Alice Stark Chair in Pharmacology. The authors acknowledge Jiayi Wang and Zhilie Li for technical assistance in data collection for this manuscript. The authors thank Drs. Jennifer Grandis and Daniel Johnson for scientific advice during the course of this work and for access to CS3D and CS3M.
J. Siegfried reports grants from NIH and University of Minnesota Foundation, grants and nonfinancial support from University of Minnesota and Masonic Cancer Center, and other from stat3 Therapeutics "licensing fees for patent," during the conduct of the study; grants from NIH outside the submitted work; and a patent 62650892 pending and licensed to stat3 Therapeutics. C. Njatcha reports a patent 62650892 pending and licensed to Stat3 Therapeutics. M. Farooqui reports grants from University of Minnesota, NIH, and University of Minnesota Foundation during the conduct of the study; grants from NIH outside the submitted work; and a patent 62650892 pending. A.A. Almotlak reports grants from University of Minnesota, NIH, and University of Minnesota foundation during the conduct of the study, as well as grants from NIH outside the submitted work. No potential conflicts of interest were disclosed by the other authors.
© 2020 American Association for Cancer Research.
PubMed: MeSH publication types
- Journal Article
- Research Support, Non-U.S. Gov't
- Research Support, N.I.H., Extramural