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Combination of Selpercatinib and Trametinib Overcomes Resistance to RET Inhibitors in RET-Mutant Medullary Thyroid Carcinoma.

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Spontaneous Murine Model of Anaplastic Thyroid Cancer
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Update on Targeted Therapy in Medullary Thyroid Cancer.

Christian Okafor1, Julie Hogan1, Margarita Raygada1

  • 1Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.

Frontiers in Endocrinology
|September 7, 2021
PubMed
Summary
This summary is machine-generated.

Medullary thyroid carcinoma (MTC) is a rare cancer. New tyrosine kinase inhibitors (TKIs) target RET mutations, but resistance and other drivers like RAS limit options, necessitating new therapeutic strategies.

Keywords:
MEN2calcitoninclinical trialsmedullary thyroid cancer (MTC)tyrosine kinase inhibitor

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Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor comprising 2-4% of thyroid cancers.
  • Activating mutations in the rearranged during transfection (RET) proto-oncogene drive all inherited and about half of sporadic MTC cases.
  • RET-targeting tyrosine kinase inhibitors (TKIs) offer systemic therapy for metastatic and progressive MTC.

Purpose of the Study:

  • To review current therapeutic strategies for MTC.
  • To discuss challenges in MTC treatment, including TKI resistance and alternative molecular drivers.
  • To highlight the need for novel therapeutic targets and improved understanding of resistance mechanisms.

Main Methods:

  • Literature review of MTC pathogenesis and treatment.
  • Analysis of clinical data regarding TKI efficacy and resistance.
  • Exploration of molecular mechanisms underlying MTC development and progression.

Main Results:

  • RET mutations are key drivers in MTC, making RET-targeted TKIs effective for many patients.
  • Acquired resistance to TKIs and alternative oncogenic drivers (e.g., RAS mutations) present significant therapeutic challenges.
  • Limited treatment options exist for patients with resistant or non-RET-driven MTC.

Conclusions:

  • While RET-targeted TKIs have improved MTC treatment, resistance remains a critical issue.
  • Further research into mechanisms of TKI resistance and identification of novel therapeutic targets are essential.
  • Improved understanding and new therapeutic strategies are needed to enhance outcomes for all MTC patients.