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

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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

DOI 10.1016/j.ccr.2014.05.019

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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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Authors: Lee, H.-J., Zhuang, G., Cao, Y., Du, P., Kim, H.-J., & Settleman, J.
Affiliations: Genentech (US)
Corresponding author: Settleman, Jeff
ORCID: Lee, Ho-June
Zhuang, Guanglei
Cao, Yi
Du, Pan
Venue: Cancer Cell
Publisher: Elsevier BV
Published: 2014-08
Volume: 26
Issue: 2
Pages: 207-221
ISSN: 1535-6108 (ISSN-L)
DOI: 10.1016/j.ccr.2014.05.019
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: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 375 d)
Locations: Cancer Cell (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Immunology and Microbiology › Immunology › 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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Drug Resistance via Feedback Activation of Stat3 in Oncogene-Addicted Cancer Cells

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