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Updated: Apr 22, 2026
Spontaneous Murine Model of Anaplastic Thyroid Cancer
Published on: February 3, 2023
Response and acquired resistance to everolimus in anaplastic thyroid cancer
Nikhil Wagle1, Brian C Grabiner, Eliezer M Van Allen
1From the Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School (N.W., E.M.V.A., N.G., R.I.H., D.J.K., P.A.J., L.A.G., J.H.L.), the Department of Medicine, Brigham and Women's Hospital and Harvard Medical School (N.W., E.M.V.A., Y.G., R.I.H., D.J.K., P.A.J., L.A.G., J.H.L.), the Departments of Pathology (J.A.B.) and Surgery (S.J.S., D.T.R.), Brigham and Women's Hospital, the Department of Medicine, Beth Israel Deaconess Medical Center (G.J.H.), and Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute (P.A.J.) - all in Boston; and Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard (N.W., E.M.V.A., A.A.-M., A.T.-W., M.R., G.G., D.J.K., S.L.C., D.M.S., L.A.G.), Whitehead Institute for Biomedical Research and the MIT Department of Biology (B.C.G., D.M.S.), and Howard Hughes Medical Institute, MIT (B.C.G., D.M.S.) - all in Cambridge, MA.
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.
Insights
Everolimus resistance in anaplastic thyroid cancer emerged due to mutations in TSC2 and MTOR. These genetic changes reveal new therapeutic strategies targeting the mTOR pathway.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Everolimus, an mTOR inhibitor, shows efficacy in tumors with mTOR pathway alterations.
- Mechanisms of everolimus resistance are not fully understood.
- Anaplastic thyroid carcinoma (ATC) is an aggressive cancer.
Observation:
- A patient with metastatic ATC experienced an 18-month response to everolimus.
- Resistance to everolimus developed in this patient.
- Whole-exome sequencing was performed on pre-treatment and resistant tumor samples.
Findings:
- A nonsense mutation in TSC2, a negative regulator of mTOR, was identified in the resistant tumor.
- This TSC2 mutation suggests a mechanism for initial sensitivity to everolimus.
- A secondary mutation in MTOR conferring resistance to allosteric mTOR inhibition was also found.
Implications:
- Understanding resistance mechanisms can guide future treatment strategies.
- The identified MTOR mutation suggests sensitivity to mTOR kinase inhibitors.
- This research provides insights into targeted therapy resistance in ATC.
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