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Updated: May 18, 2026

Spontaneous Murine Model of Anaplastic Thyroid Cancer
05:39

Spontaneous Murine Model of Anaplastic Thyroid Cancer

Published on: February 3, 2023

Understanding and overcoming innate and acquired MAPK inhibition resistance in anaplastic thyroid cancer

Peter Y F Zeng1, Jalna Meens2, Amir Hossein Karimi1

  • 1Department of Otolaryngology - Head & Neck Surgery, Western University, London, ON, Canada; Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada.

Cell Reports. Medicine
|May 16, 2026
PubMed

Insights

Anaplastic thyroid cancer (ATC) rapidly develops resistance to BRAF inhibitors. Type II RAF inhibitors like naporafenib show promise in overcoming this resistance by targeting MAPK signaling and offering new therapeutic avenues.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Anaplastic thyroid cancer (ATC) is a highly lethal malignancy.
  • BRAF V600E-mutated ATC initially responds to type I RAF inhibitors (RAFi) like dabrafenib combined with MEK inhibitors (MEKi) like trametinib, but acquired resistance is common.
  • Mechanisms of resistance involve MAPK pathway reactivation and immunosuppressive macrophages.

Purpose of the Study:

  • To investigate mechanisms of acquired resistance to RAFi/MEKi therapy in ATC.
  • To identify alternative therapeutic strategies for overcoming treatment resistance in ATC.
  • To evaluate the efficacy of type II RAF inhibitors in BRAF-mutated ATC.

Main Methods:

  • Multi-region whole-genome, whole-exome, and single-nuclei RNA sequencing of ATC tumors.
  • In vitro screening of various RAF inhibitors on ATC cell lines.
  • Assessment of drug efficacy in patient-derived xenograft models.
  • Analysis of resistance mechanisms, including genetic mutations.

Main Results:

  • MAPK pathway reactivation and immunosuppressive macrophage proliferation were identified as key mechanisms of acquired resistance.
  • ATC cell lines demonstrated high sensitivity to the type II RAFi naporafenib, which targets EphA2-mediated MAPK signaling.
  • Naporafenib, in combination with trametinib, effectively overcame both innate and acquired resistance to dabrafenib/trametinib in preclinical models.
  • A novel mechanism of acquired resistance to naporafenib involving MAST1 mutations was elucidated.

Conclusions:

  • Type II RAF inhibitors represent a promising therapeutic approach for BRAF-mutated ATC, particularly in cases of resistance to type I RAFi.
  • Understanding resistance mechanisms is crucial for developing effective combination therapies.
  • The findings support the clinical investigation of type II RAF inhibitors in thyroid cancer treatment.
Keywords:
BRAFRAF inhibitoracquired resistanceanaplastic thyroid cancermouse modelsthyroid cancertumor evolutiontumor microenvironment

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