Response and acquired resistance to everolimus in anaplastic thyroid cancer

N Engl J Med. 2014 Oct 9;371(15):1426-33. doi: 10.1056/NEJMoa1403352.

Abstract

Everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), is effective in treating tumors harboring alterations in the mTOR pathway. Mechanisms of resistance to everolimus remain undefined. Resistance developed in a patient with metastatic anaplastic thyroid carcinoma after an extraordinary 18-month response. Whole-exome sequencing of pretreatment and drug-resistant tumors revealed a nonsense mutation in TSC2, a negative regulator of mTOR, suggesting a mechanism for exquisite sensitivity to everolimus. The resistant tumor also harbored a mutation in MTOR that confers resistance to allosteric mTOR inhibition. The mutation remains sensitive to mTOR kinase inhibitors.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / therapeutic use*
  • Combined Modality Therapy
  • Drug Resistance, Neoplasm / genetics*
  • Everolimus
  • Female
  • Humans
  • Lymphatic Metastasis / pathology
  • Middle Aged
  • Mutation
  • Neoplasm Recurrence, Local / diagnostic imaging
  • Neoplasm Recurrence, Local / pathology
  • Protein Conformation
  • Radiography
  • Sirolimus / analogs & derivatives*
  • Sirolimus / therapeutic use
  • TOR Serine-Threonine Kinases / chemistry
  • TOR Serine-Threonine Kinases / genetics*
  • Thyroid Carcinoma, Anaplastic
  • Thyroid Neoplasms / diagnostic imaging
  • Thyroid Neoplasms / genetics
  • Thyroid Neoplasms / pathology
  • Thyroid Neoplasms / therapy*
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins / genetics*

Substances

  • Antineoplastic Agents
  • TSC2 protein, human
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins
  • Everolimus
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Sirolimus