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Cited by 120Cytokine Signaling Pathways and InteractionsLung Cancer Treatments and MutationsLung Cancer Research Studies

STAT3 Is Activated by JAK2 Independent of Key Oncogenic Driver Mutations in Non-Small Cell Lung Carcinoma

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Looyenga, Brendan D., Hutchings, Danielle, Cherni, Irene, Kingsley, Chris, Weiss, Glen J., MacKeigan, Jeffrey P.·2012·PLoS ONE
DOI 10.1371/journal.pone.0030820PMC PMC3271110
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Abstract

Constitutive activation of STAT3 is a common feature in many solid tumors including non-small cell lung carcinoma (NSCLC). While activation of STAT3 is commonly achieved by somatic mutations to JAK2 in hematologic malignancies, similar mutations are not often found in solid tumors. Previous work has instead suggested that STAT3 activation in solid tumors is more commonly induced by hyperactive growth factor receptors or autocrine cytokine signaling. The interplay between STAT3 activation and other well-characterized oncogenic "driver" mutations in NSCLC has not been fully characterized, though constitutive STAT3 activation has been proposed to play an important role in resistance to various small-molecule therapies that target these oncogenes. In this study we demonstrate that STAT3 is constitutively activated in human NSCLC samples and in a variety of NSCLC lines independent of activating KRAS or tyrosine kinase mutations. We further show that genetic or pharmacologic inhibition of the gp130/JAK2 signaling pathway disrupts activation of STAT3. Interestingly, treatment of NSCLC cells with the JAK1/2 inhibitor ruxolitinib has no effect on cell proliferation and viability in two-dimensional culture, but inhibits growth in soft agar and xenograft assays. These data demonstrate that JAK2/STAT3 signaling operates independent of known driver mutations in NSCLC and plays critical roles in tumor cell behavior that may not be effectively inhibited by drugs that selectively target these driver mutations.

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  • In preclinical models, non-small cell cancer cell lines with mutations in select tyrosine kinases do not exhibit decreased STAT3 activation upon treatment with erlotinib, U0126, sunitinib, or crizotinib, though other downstream effects including downregulation of phosphatidylinositol 3-kinase signaling do occur.

    “Studies in preclinical models demonstrate that non-small cell cancer cell lines with mutations in select tyrosine kinases do not exhibit decreased STAT3 activation upon treatment with the respective targeted small molecules erlotinib (EGFR), U0126 (MEK1/2), sunitinib (PDGFRA), or crizotinib (MET), though other downstream effects of these inhibitors, including downregulation of phosphatidylinositol”

    From Critical analysis of the potential for targeting STAT3 in human malignancy (2013) · cites this paper as [108]

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Authors
Looyenga, B. D., Hutchings, D., Cherni, I., Kingsley, C., Weiss, G. J., & MacKeigan, J. P.
Affiliations
  • Van Andel Institute (US)
  • Translational Genomics Research Institute (US)
Corresponding author
  • Looyenga, Brendan D.
  • MacKeigan, Jeffrey P.
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2012-02-02
Volume
7
Issue
2
Pages
e30820
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0030820
PMC
PMC3271110
OpenAlex
W2034210115
Cited by
120
References
5
Citations by year
2026: 3 · 2025: 6 · 2024: 5 · 2023: 5 · 2022: 7 · 2021: 5 · 2020: 7 · 2019: 9 · 2018: 6 · 2017: 15 · 2016: 10 · 2015: 12 · 2014: 14 · 2013: 10 · 2012: 6
FWCI
6.65
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
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 activation, JAK2, non-small cell lung cancer, KRAS mutation, tyrosine kinase mutations, ruxolitinib, JAK1/2 inhibitor, driver mutations, drug resistance, tumor growth, soft agar colony formation, tumor xenografts
MeSH terms
Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Humans, Lung Neoplasms, Mutation, Nitriles, Pyrazoles, Pyrimidines, Tumor Cells, Cultured, Signal Transduction, STAT3 Transcription Factor, Janus Kinase 2

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