Genome sequencing identifies a basis for everolimus sensitivity

Iyer G, Hanrahan AJ, Milowsky MI, Al-Ahmadie H, Scott SN, Janakiraman M, Pirun M, Sander C, Socci ND, Ostrovnaya I, Viale A, …, Solit DB · 2012 · Science · Atlas ID IYE2012

What this study shows

Genome sequencing of a single exceptional everolimus responder implicates TSC1 loss as the sensitivity basis. An n-of-1 observation, hypothesis-generating rather than confirmatory.

Abstract

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Cancer drugs often induce dramatic responses in a small minority of patients. We used whole-genome sequencing to investigate the genetic basis of a durable remission of metastatic bladder cancer in a patient treated with everolimus, a drug that inhibits the mTOR (mammalian target of rapamycin) signaling pathway. Among the somatic mutations was a loss-of-function mutation in TSC1 (tuberous sclerosis complex 1), a regulator of mTOR pathway activation.

Read the full abstract on PubMed →

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) + sequencing
Journal	Science
Year	2012
Peer reviewed	Yes
Record last updated	2026-07-29
Source	DOI 10.1126/science.1226344 · PMID 22923433 · Free full text (PMC3633467)

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 (mTOR inhibitor)
Target	mTOR / TSC1
Model	Human – metastatic bladder cancer patient + tumor sequencing
Effect	Loss-of-function TSC1 mutation explains an exceptional everolimus response; TSC1 mutated in ~8% of bladder cancers
Dose	Everolimus (mTOR inhibitor) in a phase II trial; whole-genome/targeted tumor sequencing of an exceptional responder.
Sample size	1 exceptional responder + targeted sequencing of additional bladder tumors; 3 further TSC1-nonsense tumors identified (2 minor responders: 17% and 24% regression; 1 with 7%).
Effect size	Loss-of-function TSC1 mutation underlies the exceptional everolimus response. TSC1-mutant tumors stayed on everolimus longer (7.7 vs 2.0 months, p=0.004) with improved time to recurrence (4.1 vs 1.8 months).
Limitations	Inference from rare responders; basis of mTOR-inhibitor sensitivity beyond TSC1/2 loss still incompletely understood.

In the Atlas

Links in the pathway map

Supports Everolimus inhibits mTORC1

Cite this paper

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Iyer, G., Hanrahan, A. J., Milowsky, M. I., Al-Ahmadie, H., Scott, S. N., Janakiraman, M., Pirun, M., Sander, C., Socci, N. D., Ostrovnaya, I., Viale, A., Heguy, A., Peng, L., Chan, T. A., Bochner, B., Bajorin, D. F., Berger, M. F., Taylor, B. S., & Solit, D. B. (2012). Genome sequencing identifies a basis for everolimus sensitivity. Science. https://doi.org/10.1126/science.1226344

@article{IYE2012,
  author       = {Iyer, G. and Hanrahan, A. J. and Milowsky, M. I. and Al-Ahmadie, H. and Scott, S. N. and Janakiraman, M. and Pirun, M. and Sander, C. and Socci, N. D. and Ostrovnaya, I. and Viale, A. and Heguy, A. and Peng, L. and Chan, T. A. and Bochner, B. and Bajorin, D. F. and Berger, M. F. and Taylor, B. S. and Solit, D. B.},
  title        = {{Genome sequencing identifies a basis for everolimus sensitivity}},
  journal      = {Science},
  year         = {2012},
  doi          = {10.1126/science.1226344},
  note         = {PMID: 22923433},
}

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 IYE2012) [Data set]. https://mtor-atlas.org/study/IYE2012/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_IYE2012,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record IYE2012},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/IYE2012/},
  doi          = {10.5281/zenodo.22059963}
}

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