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Overcoming resistance of targeted EGFR monotherapy by inhibition of STAT3 escape pathway in soft tissue sarcoma

Xiaochun Wang1,2, David Goldstein3, Philip J Crowe1,2

  • 1Department of Surgery, Adult Cancer Program, Lowy Cancer Research Centre, Clinical School of Prince of Wales Hospital, Faculty of Medicine, University of New South Wales, Sydney, Australia.

Oncotarget
|February 25, 2016
PubMed

Insights

Epidermal growth factor receptor (EGFR) inhibitors show limited efficacy in soft tissue sarcoma (STS). Blocking the STAT3 pathway alongside EGFR inhibition synergistically enhances anti-cancer effects in STS models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Epidermal growth factor receptor (EGFR) is frequently over-expressed in soft tissue sarcoma (STS).
  • A phase II trial revealed a low response rate for the EGFR inhibitor gefitinib in STS.
  • A secondary resistance mechanism to gefitinib in STS requires further investigation.

Purpose of the Study:

  • To identify novel resistance mechanisms to gefitinib in STS.
  • To develop strategies to enhance the efficacy of EGFR inhibition in STS.
  • To investigate the role of the STAT3 pathway in gefitinib resistance and explore combination therapy.

Main Methods:

  • Evaluated gefitinib response in seven diverse STS cell lines.
  • Assessed phosphorylated EGFR (pEGFR), pAKT, pERK, pSTAT3, and pSTAT1 levels.
  • Tested the combination of gefitinib with a STAT3 inhibitor (S3I-201) in vitro and in a fibrosarcoma xenograft mouse model.

Main Results:

  • STS cell lines exhibited resistance to gefitinib despite downstream pathway inhibition.
  • Gefitinib treatment did not decrease the pSTAT3/pSTAT1 ratio, suggesting STAT3 activation as a resistance mechanism.
  • Combination therapy with gefitinib and S3I-201 demonstrated synergistic anti-proliferative and pro-apoptotic effects.
  • Tumor growth was significantly inhibited in the combination therapy group in a mouse model.

Conclusions:

  • STAT3 pathway activation represents a secondary resistance mechanism to gefitinib in STS.
  • Combining EGFR and STAT3 inhibition can overcome gefitinib resistance in STS.
  • These findings suggest potential clinical strategies for optimizing EGFR-targeted therapy in STS.
Keywords:
EGFRSTAT3resistancesarcomatargeted therapy

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