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Cited by 63Cytokine Signaling Pathways and InteractionsLung Cancer Treatments and MutationsLung Cancer Research Studies

Small-molecule targeting of signal transducer and activator of transcription (STAT) 3 to treat non-small cell lung cancer

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Lewis, Katherine M., Bharadwaj, Uddalak, Eckols, T. Kris, Kolosov, Mikhail, Kasembeli, Moses M., Fridley, Colleen, Siller, Ricardo, Tweardy, David J.·2015·Lung Cancer
DOI 10.1016/j.lungcan.2015.09.014PMC PMC4619129
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Abstract

Objective Lung cancer is the leading cause of cancer death in both men and women. Non-small cell lung cancer (NSCLC) has an overall 5-year survival rate of 15%. While aberrant STAT3 activation has previously been observed in NSCLC, the scope of its contribution is uncertain and agents that target STAT3 for treatment are not available clinically. Methods We determined levels of activated STAT3 (STAT3 phosphorylated on Y705, pSTAT3) and the two major isoforms of STAT3 (α and β) in protein extracts of 8 NSCLC cell lines, as well as the effects of targeting STAT3 in vitro and in vivo in NSCLC cells using short hairpin (sh) RNA and two novel small-molecule STAT3 inhibitors, C188-9 and piperlongumine (PL). Results Levels of pSTAT3, STAT3α, and STATβ were increased in 7 of 8 NSCLC cell lines. Of note, levels of pSTAT3 were tightly correlated with levels of STAT3β, but not STAT3α. Targeting of STAT3 in A549 cells using shRNA decreased tSTAT3 by 75%; this was accompanied by a 47-78% reduction in anchorage-dependent and anchorage-independent growth and a 28-45% reduction in mRNA levels for anti-apoptotic STAT3 gene targets. C188-9 and PL (@30 μM) each reduced pSTAT3 levels in all NSCLC cell lines tested by ≥50%, reduced anti-apoptotic protein mRNA levels by 25-60%, and reduced both anchorage-dependent and anchorage-independent growth of NSCLC cell lines with IC50 values ranging from 3.06 to 52.44 μM and 0.86 to 11.66 μM, respectively. Treatment of nude mice bearing A549 tumor xenografts with C188-9 or PL blocked tumor growth and reduced levels of pSTAT3 and mRNA encoding anti-apoptotic proteins. Conclusion STAT3 is essential for growth of NSCLC cell lines and tumors and its targeting using C188-9 or PL may be a useful strategy for treatment.

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  • TTI-101 demonstrated potent antitumor activity in several preclinical cancer models, including NSCLC, head and neck squamous cell carcinoma, hepatocellular carcinoma, and ER-positive breast cancer resistant to inhibitors of cyclin-dependent kinases.

    “TTI-101 demonstrated potent antitumor activity in several preclinical cancer models, including NSCLC (Lewis et al., 2015), head and neck squamous cell carcinoma (Bharadwaj et al., 2016a), hepatocellular carcinoma (Jung et al., 2017), and ER-positive breast cancer resistant to inhibitors of cyclin-dependent kinases (Kettner et al., 2019).”

    From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Lewis et al., 2015

    The Abstract Results and Discussion (page numbers unavailable) report that C188-9 inhibited NSCLC cell growth and reduced tumor growth in A549 mouse xenografts. Lewis et al. do not identify C188-9 as TTI-101, so our copy does not establish the compound-name link. The other cancer models have separate citations in the citing sentence and are not attributed to Lewis et al. (LLM, conf=0.82)

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Authors
Lewis, K. M., Bharadwaj, U., Eckols, T. K., Kolosov, M., Kasembeli, M. M., Fridley, C., Siller, R., & Tweardy, D. J.
Affiliations
  • Baylor College of Medicine (US)
  • Johns Hopkins University (US)
Corresponding author
Tweardy, David J.
ORCID
Venue
Lung Cancer
Publisher
Elsevier BV
Published
2015-11
Volume
90
Issue
2
Pages
182-190
ISSN
0169-5002 (ISSN-L)
DOI
10.1016/j.lungcan.2015.09.014
PMC
PMC4619129
OpenAlex
W1909460965
Cited by
63
References
2
Citations by year
2026: 4 · 2025: 5 · 2024: 3 · 2023: 8 · 2022: 10 · 2021: 7 · 2020: 11 · 2019: 9 · 2018: 1 · 2017: 3 · 2016: 2
FWCI
0.80
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Lung Cancer (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (UL1TR000371)
  • National Heart, Lung, and Blood Institute (T32HL007747)
  • National Cancer Institute (R41CA153658, R21CA191556, P30CA125123)
  • National Institute of Allergy and Infectious Diseases (P30AI036211)
  • National Center for Research Resources (S10RR024574)
  • National Center for Advancing Translational Sciences
Topics
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
  • Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
Keywords
STAT3, non-small cell lung cancer, piperlongumine, STAT3 phosphorylation, anti-apoptotic genes, tumor growth inhibition, A549 cells, tumor xenografts
MeSH terms
Animals, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Cell Line, Cell Survival, Humans, Lung, Lung Neoplasms, Mice, Nude, Phosphorylation, Signal Transduction, Transcriptional Activation, Gene Expression Regulation, Neoplastic, Apoptosis, RNA, Small Interfering, Cell Line, Tumor, STAT3 Transcription Factor, Mice

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