Cited by 562Cytokine Signaling Pathways and InteractionsLung Cancer Treatments and MutationsMelanoma and MAPK Pathways

Drug resistance via feedback activation of Stat3 in oncogene-addicted cancer cells

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Lee, Ho-June, Zhuang, Guanglei, Cao, Yi, Du, Pan, Kim, Hyo-Jin, Settleman, Jeff·2014·Cancer Cell

Abstract

Pathway-targeted cancer drugs can produce dramatic responses that are invariably limited by the emergence of drug-resistant cells. We found that many drug-treated "oncogene-addicted" cancer cells engage a positive feedback loop leading to Stat3 activation, consequently promoting cell survival and limiting overall drug response. This was observed in cancer cells driven by diverse activated kinases, including EGFR, HER2, ALK, and MET, as well as mutant KRAS. Specifically, MEK inhibition led to autocrine activation of Stat3 via the FGF receptor and JAK kinases, and pharmacological inhibition of MEK together with JAK and FGFR enhanced tumor regression. These findings suggest that inhibition of a Stat3 feedback loop may augment the response to a broad spectrum of drugs that target pathways of oncogene addiction.

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Crossref · 10.1016/j.ccr.2014.05.019

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  • Lee et al. found that transient STAT3 activation mediated by IL-6 and FGFR in response to oncogenic kinase inhibition significantly contributes to survival of several different oncogene-addicted cancer cell lines.

    “Lee et al. found that transient STAT3 activation mediated by IL-6 and FGFR in response to oncogenic kinase inhibition significantly contributes to survival of several different oncogene-addicted cancer cell lines [67].”
  • Many oncogene-addicted cancer cells (including EGFR, HER2, ALK, MET, KRAS) engage an IL-6 dependent feedback loop leading to STAT3 activation, which promotes cell survival and limits the overall drug response.

    “Similarly, Lee et al., found that many oncogene-addicted cancer cells (including EGFR, HER2, ALK, MET, KRAS) engage an IL-6 dependent feedback loop leading to STAT3 activation [67]. This STAT3 activation promotes cell survival and limits the overall drug response.”

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Authors
Lee, H.-J., Zhuang, G., Cao, Y., Du, P., Kim, H.-J., & Settleman, J.
Affiliations
Genentech (US)
Corresponding author
Settleman, Jeff
Venue
Cancer Cell
Publisher
Elsevier BV
Published
2014-08
Volume
26
Issue
2
Pages
207-221
ISSN
1535-6108 (ISSN-L)
OpenAlex
W2102365935
Cited by
555
References
40
Citations by year
2026: 23 · 2025: 27 · 2024: 36 · 2023: 41 · 2022: 38 · 2021: 61 · 2020: 55 · 2019: 63 · 2018: 46 · 2017: 65 · 2016: 54 · 2015: 42 · 2014: 4
FWCI
26.52
Type
journal article
Language
en
Open access
Locations
  • Cancer Cell (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
Keywords
STAT3, drug resistance, oncogene addiction, positive feedback loop, MEK inhibition, JAK inhibition, fibroblast growth factor receptor, EGFR, HER2, anaplastic lymphoma kinase, MET, mutant KRAS, autocrine signaling, combination therapy, tumor regression
MeSH terms
Erlotinib Hydrochloride, Adenocarcinoma of Lung, Adenocarcinoma, Animals, Antineoplastic Agents, Cell Survival, Humans, Imidazoles, Lung Neoplasms, Mutation, Nitriles, Oncogenes, Proto-Oncogene Proteins, Pyrazoles, Pyridazines, Pyrimidines, Quinazolines, Signal Transduction, Interleukin-6, Proto-Oncogene Proteins p21(ras), Mice, SCID, Receptors, Fibroblast Growth Factor, ras Proteins, Drug Resistance, Neoplasm, Phosphatidylinositol 3-Kinases, Xenograft Model Antitumor Assays, Cell Line, Tumor, STAT3 Transcription Factor, Mice, Kaplan-Meier Estimate, Janus Kinase 1, ErbB Receptors

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