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Cited by 158HER2/EGFR in Cancer ResearchLung Cancer Treatments and MutationsCytokine Signaling Pathways and Interactions

Targeting Stat3 Abrogates EGFR Inhibitor Resistance in Cancer

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Sen, Malabika, Joyce, Sonali, Panahandeh, Mary, Li, Changyou, Thomas, Sufi M., Maxwell, Jessica, Wang, Lin, Gooding, William E., Johnson, Daniel E., Grandis, Jennifer R.·2012·Clinical Cancer Research
DOI 10.1158/1078-0432.ccr-12-0792PMC PMC3445706

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Abstract

Purpose: EGF receptor (EGFR) is upregulated in most epithelial cancers where signaling through EGFR contributes to cancer cell proliferation and survival. The limited clinical efficacy of EGFR inhibitors suggests that identification of resistance mechanisms may identify new pathways for therapeutic targeting. STAT3 is upregulated in many cancers and activated via both EGFR-dependent and -independent pathways. In the present study, we tested the consequences of STAT3 inhibition in EGFR inhibitor–resistant head and neck squamous cell carcinoma (HNSCC) and bladder cancer models to determine whether STAT3 blockade can enhance responses to EGFR targeting. Experimental Design: pSTAT3 expression was assessed in human HNSCC tumors that recurred following cetuximab treatment. Cetuximab-sensitive and -resistant cell lines were treated with a STAT3 decoy to determine EC50 concentrations and the effects on STAT3 target gene expression by Western blotting. In vivo assays included evaluation of antitumor efficacy of STAT3 decoy in cetuximab-sensitive and -resistant models followed by immunoblotting for STAT3 target protein expression. Results: Targeting STAT3 with a STAT3 decoy reduced cellular viability and the expression of STAT3 target genes in EGFR inhibitor resistance models. The addition of a STAT3 inhibitor to EGFR blocking strategies significantly enhanced antitumor effects in vivo. Biopsies from HNSCC tumors that recurred following cetuximab treatment showed increased STAT3 activation compared with pretreatment biopsies. Conclusions: These results suggest that STAT3 activation contributes to EGFR inhibitor resistance both in HNSCC and bladder cancer where concomitant targeting of STAT3 may represent an effective treatment strategy. Clin Cancer Res; 18(18); 4986–96. ©2012 AACR.

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  • Activation of STAT3 is associated with emergent resistance to targeted therapies and decreased patient survival.

    “In addition, activation of STAT3 is associated with emergent resistance to targeted therapies and decreased patient survival.39,40”

    From Critical analysis of the potential for targeting STAT3 in human malignancy (2013) · cites this paper as [40]

    The Introduction and Discussion associate STAT3 activation with resistance to EGFR inhibitors, including acquired resistance, and the Discussion reports increased STAT3 activation in resistant cancer models. Neither section links STAT3 activation to decreased patient survival. Page numbers are unavailable in our copy. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • STAT3 inhibition may be effective at overcoming acquired resistance or as adjuvant therapy to prevent recurrence.

    “These results suggest that STAT3 inhibition may be effective at overcoming acquired resistance or as adjuvant therapy to prevent recurrence.40”

    From Critical analysis of the potential for targeting STAT3 in human malignancy (2013) · cites this paper as [40]

    The Discussion (page not provided) reports that targeting STAT3 sensitized EGFR-inhibitor-resistant cells to treatment and suggests it may overcome therapeutic resistance. The Results describe increased pSTAT3 in tumors that recurred after cetuximab, but the paper does not propose STAT3 inhibition as adjuvant therapy to prevent recurrence. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Combination of STAT3 inhibition with EGFR blockade significantly enhances antitumor effects in vivo relative to EGFR blockade alone.

    “Importantly, a combination of STAT3 inhibition with EGFR blockade significantly enhances antitumor effects in vivo relative to EGFR blockade alone, suggesting that the efficacy of already existing (and approved) drugs may be significantly increased by concomitant treatment with STAT3 inhibitors.40”

    From Critical analysis of the potential for targeting STAT3 in human malignancy (2013) · cites this paper as [40]

  • Efficacy of already existing (and approved) drugs may be significantly increased by concomitant treatment with STAT3 inhibitors.

    “Importantly, a combination of STAT3 inhibition with EGFR blockade significantly enhances antitumor effects in vivo relative to EGFR blockade alone, suggesting that the efficacy of already existing (and approved) drugs may be significantly increased by concomitant treatment with STAT3 inhibitors.40”

    From Critical analysis of the potential for targeting STAT3 in human malignancy (2013) · cites this paper as [40]

  • Biopsies of recurrent HNSCC following cetuximab treatment exhibit elevated pSTAT3 relative to pretreatment samples.

    “Biopsies of recurrent HNSCC following treatment with cetuximab, a Food and Drug Administration-approved monoclonal antibody targeting EGFR, exhibit elevated pSTAT3 relative to pretreatment samples.”

    From Critical analysis of the potential for targeting STAT3 in human malignancy (2013) · cites this paper as [40]

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Cited by

Sorted by citations

Authors
Sen, M., Joyce, S., Panahandeh, M., Li, C., Thomas, S. M., Maxwell, J., Wang, L., Gooding, W. E., Johnson, D. E., & Grandis, J. R.
Affiliations
University of Pittsburgh (US)
Corresponding author
Grandis, Jennifer R.
ORCID
Venue
Clinical Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2012-09-15
Volume
18
Issue
18
Pages
4986-4996
ISSN
  • 1078-0432 (ISSN-L)
  • 1557-3265
DOI
10.1158/1078-0432.ccr-12-0792
PMC
PMC3445706
OpenAlex
W2115009923
Cited by
158
References
2
Citations by year
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FWCI
9.66
Type
journal article
Language
en
Open access
Locations
  • Clinical Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
National Cancer Institute (R01CA137260, R01CA098372, P50CA097190)
Topics
  • Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
Keywords
STAT3, EGFR inhibitor resistance, cetuximab, head and neck squamous cell carcinoma, bladder cancer, combination therapy, STAT3 target genes, tumor recurrence, epithelial cancers
MeSH terms
Cetuximab, Erlotinib Hydrochloride, Squamous Cell Carcinoma of Head and Neck, Animals, Antibodies, Monoclonal, Antineoplastic Agents, Carcinoma, Squamous Cell, Female, Head and Neck Neoplasms, Humans, Mice, Nude, Phosphorylation, Quinazolines, Signal Transduction, Gene Expression Regulation, Neoplastic, Drug Resistance, Neoplasm, Xenograft Model Antitumor Assays, Cell Line, Tumor, STAT3 Transcription Factor, Mice, Antibodies, Monoclonal, Humanized, ErbB Receptors

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