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Vemurafenib activates the sonic hedgehog pathway and promotes thyroid cancer stem cell self-renewal

Yurong Lu1, Yuqing Zhao1, Penggang Liu1

  • 1Institute of Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu Province, China.

Endocrine-Related Cancer
|August 29, 2023
PubMed

Insights

Vemurafenib (PLX4032) increases cancer stem cell activity in thyroid cancer by activating the sonic hedgehog pathway. Combining vemurafenib with a Gli1 inhibitor overcomes this resistance, improving treatment efficacy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • B-Raf kinase inhibitors show limited efficacy in BRAF-mutated thyroid cancer.
  • Cancer stem cells (CSCs) are implicated in tumor recurrence and drug resistance.

Purpose of the Study:

  • To investigate the role of CSCs in the limited efficacy of B-Raf kinase inhibitors in thyroid cancer.
  • To elucidate the mechanisms by which vemurafenib affects CSCs and to explore combination therapies.

Main Methods:

  • Treatment of anaplastic thyroid cancer cell lines (SW1736, 8505C) and melanoma cells (A375) with vemurafenib (PLX4032).
  • Assessment of stemness-related gene expression (Gli1, Snail, BMI1, SOX2) and CSC self-renewal markers (ALDH-positive cells, thyrospheres).
  • Investigation of signaling pathways (PI3K, MAPK, HER3, Shh) and combination therapy with Gli1 inhibitor (GANT61) in vitro and in vivo xenograft models.

Main Results:

  • Vemurafenib induced stemness genes and promoted CSC self-renewal in thyroid cancer cells, but not in melanoma cells.
  • Mechanistically, vemurafenib activated PI3K/MAPK pathways via HER3, leading to Gli1 cross-activation.
  • Gli1 inhibition by GANT61 blocked stemness gene expression and enhanced vemurafenib's antitumor activity in combination therapy.

Conclusions:

  • Thyroid cancer's poor response to B-Raf inhibitors is linked to CSC activation via the sonic hedgehog pathway.
  • Combined targeting of B-Raf and the Shh pathway presents a promising strategy to overcome drug resistance in thyroid cancer.
Keywords:
Gli1PLX4032cancer stem cellssonic hedgehogthyroid cancer

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