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

Wagle N, Grabiner BC, Van Allen EM, Hodis E, Jacobus S, Supko JG, Stewart M, Choueiri TK, Gandhi L, Cleary JM, Elfiky AA, …, Rosenberg JE · 2014 · Cancer discovery · Atlas ID WAG2014

What this study shows

Two concurrent activating MTOR mutations are implicated in an extraordinary clinical response to rapalog therapy. Single-patient observation: hypothesis-generating, not evidence of a general response predictor.

Abstract

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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.

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At a glance

Evidence type	H Human study Marked H because it is direct evidence from a human clinical trial or human cohort; the code names the kind of study, not its quality -- a small, well-run trial is still H.
Study type	3 - Human Observational
Model system	Human (patient)
Journal	Cancer discovery
Year	2014
Peer reviewed	Yes
Record last updated	2026-07-29
Source	DOI 10.1158/2159-8290.CD-13-0353 · PMID 24625776 · Free full text (PMC4122326)

Extracted findings

These fields were extracted from the paper with AI assistance and have not been checked against the source. Read them as a pointer into the paper, not as curated claims; where they disagree with the curated summary above, the curated summary stands.

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
Dose	Pazopanib 400 mg daily + everolimus 5 mg daily (MTD; 600 mg + 5 mg gave dose-limiting toxicities); phase I.
Sample size	9 patients enrolled (5 urothelial, others lung/carcinoid); an exceptional responder analyzed by sequencing.
Effect size	Activating mTOR mutations underlie the extraordinary response to everolimus+pazopanib. 5/9 patients had grade >=3 toxicity (56%, 95% CI 21.2-86.3%); everolimus AUC 41% higher when combined with pazopanib.
Limitations	Inference from a single exceptional responder; basis of mTOR-inhibitor sensitivity incompletely understood; short drug exposure in some.

In the Atlas

Cite this paper

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Wagle, N., Grabiner, B. C., Van Allen, E. M., Hodis, E., Jacobus, S., Supko, J. G., Stewart, M., Choueiri, T. K., Gandhi, L., Cleary, J. M., Elfiky, A. A., Taplin, M. E., Stack, E. C., Signoretti, S., Loda, M., Shapiro, G. I., Sabatini, D. M., Lander, E. S., Gabriel, S. B., Kantoff, P. W., Garraway, L. A., & Rosenberg, J. E. (2014). Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib. Cancer discovery. https://doi.org/10.1158/2159-8290.CD-13-0353

@article{WAG2014,
  author       = {Wagle, N. and Grabiner, B. C. and Van Allen, E. M. and Hodis, E. and Jacobus, S. and Supko, J. G. and Stewart, M. and Choueiri, T. K. and Gandhi, L. and Cleary, J. M. and Elfiky, A. A. and Taplin, M. E. and Stack, E. C. and Signoretti, S. and Loda, M. and Shapiro, G. I. and Sabatini, D. M. and Lander, E. S. and Gabriel, S. B. and Kantoff, P. W. and Garraway, L. A. and Rosenberg, J. E.},
  title        = {{Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib}},
  journal      = {Cancer discovery},
  year         = {2014},
  doi          = {10.1158/2159-8290.CD-13-0353},
  note         = {PMID: 24625776},
}

Cite this Atlas record

The record is the Atlas's own work — the evidence label, the extracted findings and the links. It is cited as part of the dataset, not as the paper.

Barton, O. (2026). Oliver's mTOR Atlas (record WAG2014) [Data set]. https://mtor-atlas.org/study/WAG2014/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_WAG2014,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record WAG2014},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/WAG2014/},
  doi          = {10.5281/zenodo.22059963}
}

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