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.

Significance: The study of exceptional responders represents a promising approach to better understanding the mechanisms that underlie sensitivity to targeted anticancer therapies. Here, we identify two activating mTOR mutations in a patient with exquisite sensitivity to everolimus and pazopanib, suggesting an approach to identifying patients who might benefit most from mTOR inhibitors. Cancer Discov; 4(5); 546–53. ©2014 AACR.

See related commentary by Rejto and Abraham, p. 513

This article is highlighted in the In This Issue feature, p. 495