Send to

Choose Destination
Cancer Discov. 2014 May;4(5):546-53. doi: 10.1158/2159-8290.CD-13-0353. Epub 2014 Mar 13.

Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib.

Author information

Departments of 1Medical Oncology and 2Biostatistics and Computational Biology, 3Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute; Departments of 4Medicine and 5Pathology, Brigham and Women's Hospital, Harvard Medical School; 6Division of Hematology/Oncology, Massachusetts General Hospital, Boston; 7Broad Institute of Harvard and MIT; 8Department of Biology, Whitehead Institute for Biomedical Research; 9Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts; and 10Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.


Understanding the genetic mechanisms of sensitivity to targeted anticancer therapies may improve patient selection, response to therapy, and rational treatment designs. One approach to increase this understanding involves detailed studies of exceptional responders: rare patients with unexpected exquisite sensitivity or durable responses to therapy. We identified an exceptional responder in a phase I study of pazopanib and everolimus in advanced solid tumors. Whole-exome sequencing of a patient with a 14-month complete response on this trial revealed two concurrent mutations in mTOR, the target of everolimus. In vitro experiments demonstrate that both mutations are activating, suggesting a biologic mechanism for exquisite sensitivity to everolimus in this patient. The use of precision (or "personalized") medicine approaches to screen patients with cancer for alterations in the mTOR pathway may help to identify subsets of patients who may benefit from targeted therapies directed against mTOR.

[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Publication types

MeSH terms


Grant support

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center