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

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.

• Authors: Nikhil Wagle, Brian C Grabiner, Eliezer M Van Allen, Eran Hodis, Susanna Jacobus, Jeffrey G Supko, Michelle Stewart, Toni K Choueiri, Leena Gandhi, James M Cleary, Aymen A Elfiky, Mary Ellen Taplin, Edward C Stack, Sabina Signoretti, Massimo Loda, Geoffrey I Shapiro, David M Sabatini, Eric S Lander, Stacey B Gabriel, Philip W Kantoff, Levi A Garraway, Jonathan E Rosenberg
• Journal: Cancer discovery (Cancer Discov) Vol. 4 Issue 5 Pg. 546-53 (May 2014) ISSN: 2159-8290 [Electronic] United States
• PMID: 24625776 (Publication Type: Case Reports, Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Indazoles
• Pyrimidines
• Sulfonamides
• pazopanib
• Everolimus
• MTOR protein, human
• TOR Serine-Threonine Kinases

Topics

• Aged
• Antineoplastic Agents (administration & dosage, pharmacokinetics, therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, therapeutic use)
• Carcinoma, Transitional Cell (drug therapy, genetics)
• Drug Administration Schedule
• Everolimus (administration & dosage, pharmacokinetics, therapeutic use)
• Female
• High-Throughput Nucleotide Sequencing
• Humans
• Indazoles
• Lymphatic Metastasis (diagnostic imaging, genetics)
• Male
• Middle Aged
• Mutation
• Precision Medicine
• Pyrimidines (administration & dosage, pharmacokinetics, therapeutic use)
• Radionuclide Imaging
• Sequence Analysis, DNA
• Sulfonamides (administration & dosage, pharmacokinetics, therapeutic use)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, chemistry, genetics)
• Urinary Bladder Neoplasms (drug therapy, genetics)