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Response and Acquired Resistance to Everolimus in Anaplastic Thyroid Cancer

Author(s)
Van Allen, Eliezer M.; Amin-Mansour, Ali; Taylor-Weiner, Amaro; Rosenberg, Mara; Barletta, Justine A.; Guo, Yanan; Swanson, Scott J.; Ruan, Daniel T.; Hanna, Glenn J.; Haddad, Robert I.; Kwiatkowski, David J.; Jänne, Pasi A.; Lorch, Jochen H.; Wagle, Nikhil; Grabiner, Brian; Gray, Nathanael S; Getz, Gad Asher; Carter, Scott; Sabatini, David; Garraway, Levi A.; ... Show more Show less
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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.
Date issued
2014-10
URI
http://hdl.handle.net/1721.1/108362
Department
Massachusetts Institute of Technology. Institute for Medical Engineering & Science; Broad Institute of MIT and Harvard; Massachusetts Institute of Technology. Department of Biology
Journal
New England Journal of Medicine
Publisher
New England Journal of Medicine
Citation
Wagle, Nikhil; Grabiner, Brian C.; Van Allen, Eliezer M.; Amin-Mansour, Ali; Taylor-Weiner, Amaro; Rosenberg, Mara; Gray, Nathanael et al. “Response and Acquired Resistance to Everolimus in Anaplastic Thyroid Cancer.” New England Journal of Medicine 371, no. 15 (October 2014): 1426–1433. © New England Journal of Medicine
Version: Final published version
ISSN
0028-4793
1533-4406

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