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RET alterations in thyroid cancer: Molecular mechanisms, targeted therapies, and emerging resistance

Shujing Mao1, Nanfen Zhou1, Liyuan Huang1

  • 1Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.

Critical Reviews in Oncology/Hematology
|July 28, 2026
PubMed

Insights

RET alterations drive thyroid cancer, with fusions in papillary and mutations in medullary types. Targeted therapies are evolving from broad kinase inhibitors to selective drugs, with next-generation inhibitors addressing resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • RET alterations (fusions, mutations) are key drivers in thyroid cancer.
  • RET fusions are common in papillary thyroid carcinoma, while mutations are prevalent in medullary thyroid carcinoma.
  • RET is a significant therapeutic target in thyroid cancer treatment.

Purpose of the Study:

  • To provide an overview of RET alterations in thyroid cancer.
  • To discuss the evolution of targeted therapies for RET-driven thyroid cancer.
  • To highlight emerging resistance mechanisms and next-generation inhibitors.

Main Methods:

  • Literature review of molecular mechanisms of RET alterations.
  • Analysis of targeted therapies, including multikinase and selective tyrosine kinase inhibitors.
  • Examination of acquired drug resistance and novel therapeutic strategies.

Main Results:

  • RET fusions and mutations characterize distinct thyroid cancer subtypes.
  • Early inhibitors (vandetanib, cabozantinib) showed limited efficacy due to off-target effects.
  • Selective inhibitors (selpercatinib, pralsetinib) improved outcomes, but resistance via mutations is emerging.
  • Next-generation inhibitors (zeteletinib, SYHA1815) are under investigation to overcome resistance.

Conclusions:

  • Understanding RET alteration mechanisms is crucial for effective thyroid cancer treatment.
  • The therapeutic landscape for RET-altered thyroid cancer is rapidly advancing.
  • Overcoming acquired resistance is essential for durable responses to targeted therapies.
Keywords:
Drug resistanceRET fusionRET mutationTargeted therapyThyroid cancer

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