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STAT3 mediates resistance to MEK inhibitor through microRNA miR-17

Bingbing Dai1, Jieru Meng, Michael Peyton

  • 1Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. bdai@mdanderson.org

Cancer Research
|March 30, 2011
PubMed

Insights

AZD6244 (MEK inhibitor) resistance in lung cancer involves STAT3 pathway activation and miR-17 overexpression, which blocks BIM. Inhibiting STAT3 or miR-17 sensitizes cells to AZD6244, offering new treatment strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • AZD6244 (MEK inhibitor) shows promise in clinical trials for cancer treatment.
  • Mechanisms of intrinsic resistance to MEK inhibitors are not fully understood.
  • Understanding resistance is crucial for developing effective cancer therapies.

Purpose of the Study:

  • To elucidate molecular mechanisms of intrinsic resistance to MEK inhibition.
  • To identify biomarkers predictive of sensitivity or resistance to AZD6244.
  • To explore therapeutic strategies to overcome MEK inhibitor resistance.

Main Methods:

  • Analysis of 38 lung cancer cell lines treated with AZD6244.
  • Genome-wide gene expression profiling.
  • Pathway analysis (Ingenuity Pathway Analysis).
  • Inhibition of STAT3 pathway using small molecule inhibitor (JSI-124) and siRNA.
  • Assessment of microRNA (miR-17) role in resistance.

Main Results:

  • STAT3 pathway activation correlated with resistance to AZD6244.
  • Inhibiting STAT3 or miR-17 sensitized lung cancer cells to AZD6244.
  • STAT3 inhibition and miR-17 inhibition induced BIM expression and PARP cleavage.
  • STAT3-mediated miR-17 overexpression was identified as a key mechanism of resistance.
  • Overexpression of miR-17 blocked BIM expression, leading to AZD6244 resistance.

Conclusions:

  • STAT3-mediated miR-17 overexpression is a critical mechanism conferring resistance to MEK inhibitors like AZD6244.
  • Combining AZD6244 with STAT3 or miR-17 inhibitors represents a potential therapeutic strategy to overcome resistance.
  • Targeting the STAT3/miR-17/BIM axis offers novel approaches for lung cancer treatment.

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