Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib Academic Article uri icon

Overview

MeSH Major

  • Antineoplastic Agents
  • Antineoplastic Combined Chemotherapy Protocols
  • Carcinoma, Transitional Cell
  • Everolimus
  • Pyrimidines
  • Sulfonamides
  • TOR Serine-Threonine Kinases
  • Urinary Bladder Neoplasms

abstract

  • 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.

publication date

  • January 2014

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4122326

Digital Object Identifier (DOI)

  • 10.1158/2159-8290.CD-13-0353

PubMed ID

  • 24625776

Additional Document Info

start page

  • 546

end page

  • 53

volume

  • 4

number

  • 5