An activating MTOR mutation underlies an extraordinary clinical response to rapalog therapy.
| Evidence tier | B Direct human evidence |
| Study type | 3 - Human Observational |
| Model system | Human (patient) |
| Journal | Cancer discovery |
| Year | 2014 |
| Peer reviewed | Yes |
| Source | DOI 10.1158/2159-8290.CD-13-0353 · PMID 24625776 · Free full text (PMC4122326) |
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.
| Intervention | Everolimus + pazopanib (mTOR inhibition) |
| Target | mTOR (activating mutations) |
| Model | Human (patient, phase I) |
| Effect | Activating mTOR mutations underlie an extraordinary response to everolimus in a phase I patient |