STAT3 cyclic decoy demonstrates robust antitumor effects in non–small cell lung cancer

Christian Njatcha, Mariya Farooqui, Adam Kornberg, Daniel E. Johnson, Jennifer R. Grandis, Jill M. Siegfried

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


Constitutively activated STAT3 plays a critical role in non–small cell lung carcinoma (NSCLC) progression by mediating proliferation and survival. STAT3 activation in normal cells is transient, making it an attractive target for NSCLC therapy. The therapeutic potential of blocking STAT3 in NSCLC was assessed utilizing a decoy approach by ligating a double-stranded 15-mer oligonucleotide that corresponds to the STAT3 response element of STAT3-target genes, to produce a cyclic STAT3 decoy (CS3D). The decoy was evaluated using NSCLC cells containing either wild-type EGFR (201T) or mutant EGFR with an additional EGFRi resistance mutation (H1975). These cells are resistant to EGFR inhibitors and require an alternate therapeutic approach. CS3D activity was compared with an inactive cyclic control oligonucleotide (CS3M) that differs by a single base pair, rendering it unable to bind to STAT3 protein. Transfection of 0.3 mmol/L of CS3D caused a 50% inhibition in proliferation in 201T and H1975 cells, relative to CS3M, and a 2-fold increase in apoptotic cells. Toxicity was minimal in normal cells. CS3D treatment caused a significant reduction of mRNA and protein expression of the STAT3 target gene c-Myc and inhibited colony formation by 70%. The active decoy decreased the nuclear pool of STAT3 compared with the mutant. In a xenograft model, treatments with CS3D (5 mg/kg) caused a potent 96.5% and 81.7% reduction in tumor growth in 201T (P < 0.007) and H1975 models (P < 0.0001), respectively, and reduced c-Myc and p-STAT3 proteins. Targeting STAT3 with the cyclic decoy could be an effective therapeutic strategy for NSCLC.

Original languageEnglish (US)
Pages (from-to)1917-1926
Number of pages10
JournalMolecular Cancer Therapeutics
Issue number9
StatePublished - Sep 2018

Bibliographical note

Funding Information:
This research was funded in part by a philanthropic gift from the 5th District Eagles of Minnesota to the Masonic Cancer Center (to J.M. Siegfried) and by P50 CA097190 (to J.R. Grandis) from NCI and an American Cancer Society Professorship (to J.R. Grandis). C. Njatcha was supported by a fellowship from a T32 Cancer Biology Training Grant (T32 CA009138) from the NCI and by an F31 individual fellowship (F31 CA213982) from the NCI. J.M. Siegfried was supported by the Frederick & Alice Stark Chair in Pharmacology. A. Kornberg was supported by an undergraduate summer fellowship from grant R25 CA200508 (to JMS) from the NCI.

Publisher Copyright:
© 2018 American Association for Cancer Research.


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