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Updated: Feb 8, 2026

An Orthotopic Mouse Model of Anaplastic Thyroid Carcinoma
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IL6/STAT3 axis mediates resistance to BRAF inhibitors in thyroid carcinoma cells

Tiziana Notarangelo1, Lorenza Sisinni1, Stefania Trino1

  • 1Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture, PZ, Italy.

Cancer Letters
|July 4, 2018
PubMed

Insights

BRAF-mutated thyroid cancers resist BRAF inhibitors (BRAFi) partly due to IL6/STAT3 pathway activation. Blocking IL6/STAT3 alongside BRAFi enhances cancer cell growth inhibition.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • BRAF mutations are common in thyroid carcinomas (TCs), but BRAF inhibitors (BRAFi) show limited efficacy compared to melanoma.
  • TCs develop acquired resistance to BRAFi through alternative signaling pathway activation.

Purpose of the Study:

  • To investigate the signaling pathways involved in BRAF inhibitor resistance in BRAF V600E mutated thyroid cancer cells.
  • To identify potential therapeutic strategies to overcome BRAFi resistance.

Main Methods:

  • Whole-genome gene expression analysis of TC BRAF V600E cells treated with PLX4032 (a BRAFi).
  • Assessed the role of the JAK/STAT and IL6/STAT3 signaling pathways.
  • Utilized siRNA or pharmacological inhibition for STAT3, tocilizumab (anti-IL6 receptor antibody), and PLX4032.

Main Results:

  • PLX4032 treatment led to the upregulation of the IL6/STAT3 axis, impairing its cytostatic activity.
  • PLX4032 enhanced IL6 secretion, causing STAT3 upregulation, ERK activation, and reduced BRAFi sensitivity.
  • Combined blockade of STAT3 or IL6 signaling with BRAF inhibition improved cell cycle arrest compared to BRAFi alone.

Conclusions:

  • The IL6/STAT3 signaling pathway plays a critical role in modulating the response of BRAF V600E TCs to BRAFi.
  • Targeting IL6 signaling represents a promising strategy to enhance the efficacy of BRAFi in BRAF V600E thyroid cancer.
Keywords:
IL6PLX4032STAT3Thyroid carcinomaTocilizumab

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