Response and acquired resistance to everolimus in anaplastic thyroid cancer

Nikhil Wagle, Brian C. Grabiner, Eliezer M. Van Allen, Ali Amin-Mansour, Amaro Taylor-Weiner, Mara Rosenberg, Nathanael Gray, Justine A. Barletta, Yanan Guo, Scott J. Swanson, Daniel T. Ruan, Glenn J. Hanna, Robert I. Haddad, Gad Getz, David J. Kwiatkowski, Scott L. Carter, David M. Sabatini, Pasi A. Jänne, Levi A. Garraway, Jochen H. Lorch*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

218 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1426-1433
Number of pages8
JournalNew England Journal of Medicine
Volume371
Issue number15
DOIs
StatePublished - Oct 9 2014
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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