期刊
NEW ENGLAND JOURNAL OF MEDICINE
卷 371, 期 15, 页码 1426-1433出版社
MASSACHUSETTS MEDICAL SOC
DOI: 10.1056/NEJMoa1403352
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资金
- Next Generation Fund at the Broad Institute of Massachusetts Institute of Technology and Harvard
- Novartis Pharmaceuticals
- Starr Cancer Consortium
- National Cancer Institute
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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