Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas
Open accessAbstract
Persistently activated or tyrosine-phosphorylated STAT3 (pSTAT3) is found in 50% of lung adenocarcinomas. pSTAT3 is found in primary adenocarcinomas and cell lines harboring somatic-activating mutations in the tyrosine kinase domain of EGFR. Treatment of cell lines with either an EGFR inhibitor or an src kinase inhibitor had no effect on pSTAT3 levels, whereas a pan-JAK inhibitor (P6) blocked activation of STAT3 and inhibited tumorigenesis. Cell lines expressing these persistently activated mutant EGFRs also produced high IL-6 levels, and blockade of the IL-6/gp130/JAK pathway led to a decrease in pSTAT3 levels. In addition, reduction of IL-6 levels by RNA interference led to a decrease in tumorigenesis. Introduction of persistently activated EGFR into immortalized breast epithelial cells led to tumorigenesis, IL-6 expression, and STAT3 activation, all of which could be inhibited with P6 or gp130 blockade. Furthermore, inhibition of EGFR activity in multiple cell lines partially blocked transcription of IL-6 and concurrently decreased production and release of IL-6. Finally, immunohistochemical analysis revealed a positive correlation between pSTAT3 and IL-6 positivity in primary lung adenocarcinomas. Therefore, mutant EGFR could activate the gp130/JAK/STAT3 pathway by means of IL-6 upregulation in primary human lung adenocarcinomas, making this pathway a potential target for cancer treatment.
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IL-6 and STAT3 are required for activated mutant EGFR-induced lung cancer and colitis-associated cancer.
“The requirement of IL-6 and STAT3 for activated mutant EGFR-induced lung cancer and colitis-associated cancer has also been demonstrated (18, 257).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [257]
Activated mutant EGFR in lung cancer induces IL-6 gene expression to activate constitutive IL-6-STAT3 signaling in a paracrine and autocrine manner.
“Similarly, activated mutant EGFR in lung cancer induces IL-6 gene expression to activate constitutive IL-6–STAT3 signaling in a paracrine and autocrine manner (257).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [257]
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- Authors
- Gao, S. P., Mark, K. G., Leslie, K., Pao, W., Motoi, N., Gerald, W. L., Travis, W. D., Bornmann, W., Veach, D., Clarkson, B., & Bromberg, J. F.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Bromberg, Jacqueline F.
- Venue
- Journal of Clinical Investigation
- Published
- 2007-12-03
- Volume
- 117
- Issue
- 12
- Pages
- 3846-3856
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC2096430
- OpenAlex
- W2099805317
- Cited by
- 666
- References
- 7
- Citations by year
- 2026: 14 · 2025: 14 · 2024: 9 · 2023: 29 · 2022: 19 · 2021: 35 · 2020: 47 · 2019: 40 · 2018: 34 · 2017: 42 · 2016: 47 · 2015: 52 · 2014: 59 · 2013: 41 · 2012: 49
- FWCI
- 15.35
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- Breast Cancer Alliance
- New York State Department of Health
- National Institutes of Health
- National Cancer Institute (R01CA087637, R01 CA87637, P01CA064593, P30CA008748)
- 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 › HER2/EGFR in Cancer Research
- Keywords
- EGFR mutation, STAT3 activation, interleukin-6, lung adenocarcinoma, tyrosine kinase domain, JAK inhibitors, carcinogenesis, EGFR inhibitors, breast epithelial cells, cancer therapy targets
- MeSH terms
- Interleukin-6 Inhibitors, Adenocarcinoma, Animals, Enzyme Inhibitors, Female, Humans, Lung Neoplasms, Mice, Nude, Mutation, Neoplasm Transplantation, Phosphorylation, Transcription, Genetic, Signal Transduction, Interleukin-6, Gene Expression Regulation, Neoplastic, RNA, Small Interfering, Cell Line, Tumor, STAT3 Transcription Factor, Cytokine Receptor gp130, Mice, Janus Kinases, ErbB Receptors
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