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

doi:10.1056/NEJMoa1403352

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 journal › Article › peer-review

240 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 language	English (US)
Pages (from-to)	1426-1433
Number of pages	8
Journal	New England Journal of Medicine
Volume	371
Issue number	15
DOIs	https://doi.org/10.1056/NEJMoa1403352
State	Published - Oct 9 2014
Externally published	Yes

ASJC Scopus subject areas

Medicine(all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Wagle, N., Grabiner, B. C., Van Allen, E. M., Amin-Mansour, A., Taylor-Weiner, A., Rosenberg, M., Gray, N., Barletta, J. A., Guo, Y., Swanson, S. J., Ruan, D. T., Hanna, G. J., Haddad, R. I., Getz, G., Kwiatkowski, D. J., Carter, S. L., Sabatini, D. M., Jänne, P. A., Garraway, L. A., & Lorch, J. H. (2014). Response and acquired resistance to everolimus in anaplastic thyroid cancer. New England Journal of Medicine, 371(15), 1426-1433. https://doi.org/10.1056/NEJMoa1403352

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title = "Response and acquired resistance to everolimus in anaplastic thyroid cancer",

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.",

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

year = "2014",

month = oct,

day = "9",

doi = "10.1056/NEJMoa1403352",

language = "English (US)",

volume = "371",

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Wagle, N, Grabiner, BC, Van Allen, EM, Amin-Mansour, A, Taylor-Weiner, A, Rosenberg, M, Gray, N, Barletta, JA, Guo, Y, Swanson, SJ, Ruan, DT, Hanna, GJ, Haddad, RI, Getz, G, Kwiatkowski, DJ, Carter, SL, Sabatini, DM, Jänne, PA, Garraway, LA & Lorch, JH 2014, 'Response and acquired resistance to everolimus in anaplastic thyroid cancer', New England Journal of Medicine, vol. 371, no. 15, pp. 1426-1433. https://doi.org/10.1056/NEJMoa1403352

TY - JOUR

T1 - Response and acquired resistance to everolimus in anaplastic thyroid cancer

AU - Wagle, Nikhil

AU - Grabiner, Brian C.

AU - Van Allen, Eliezer M.

AU - Amin-Mansour, Ali

AU - Taylor-Weiner, Amaro

AU - Rosenberg, Mara

AU - Gray, Nathanael

AU - Barletta, Justine A.

AU - Guo, Yanan

AU - Swanson, Scott J.

AU - Ruan, Daniel T.

AU - Hanna, Glenn J.

AU - Haddad, Robert I.

AU - Getz, Gad

AU - Kwiatkowski, David J.

AU - Carter, Scott L.

AU - Sabatini, David M.

AU - Jänne, Pasi A.

AU - Garraway, Levi A.

AU - Lorch, Jochen H.

PY - 2014/10/9

Y1 - 2014/10/9

N2 - 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.

AB - 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.

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Response and acquired resistance to everolimus in anaplastic thyroid cancer

Abstract

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