Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer

Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, Alimonti A, Egia A, Sasaki AT, Thomas G, Kozma SC, Papa A, …, Pandolfi PP · 2008 · The Journal of clinical investigation · Atlas ID CAR2008

What this study shows

mTORC1 inhibition activates the MAPK pathway via a PI3K-dependent feedback loop. Seen in tumour biopsies from patients with advanced solid tumours treated with RAD001 (everolimus), where the rise depended on the dosing schedule, and in a mouse prostate cancer model, xenografts and cell lines.

Abstract

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Numerous studies have established a causal link between aberrant mammalian target of rapamycin (mTOR) activation and tumorigenesis, indicating that mTOR inhibition may have therapeutic potential. In this study, we show that rapamycin and its analogs activate the MAPK pathway in human cancer, in what represents a novel mTORC1-MAPK feedback loop. We found that tumor samples from patients with biopsy-accessible solid tumors of advanced disease treated with RAD001, a rapamycin derivative, showed an administration schedule-dependent increase in activation of the MAPK pathway.

Read the full abstract on PubMed →

At a glance

Evidence type	M Molecular — cells, biochemistry, structure Marked M because it is molecular or in-vitro work (model: Patient tumour biopsies (advanced solid tumours, RAD001); mouse prostate cancer model; xenografts; human cancer and normal cell lines) rather than a whole-organism health-outcome study. That is often exactly where causal biology gets established -- the code says which system the finding was shown in, and nothing about how good the work is.
Study type	5 - Mechanistic / In Vitro
Model system	Patient tumour biopsies (advanced solid tumours, RAD001); mouse prostate cancer model; xenografts; human cancer and normal cell lines
Journal	The Journal of clinical investigation
Year	2008
Peer reviewed	Yes
Record last updated	2026-10-01
Source	DOI 10.1172/JCI34739 · PMID 18725988 · Free full text (PMC2518073)

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	mTOR inhibition (rapamycin/rapalogs)
Target	mTORC1 / MAPK / PI3K
Model	Human (patient tumour biopsies on RAD001); mouse; human cells
Effect	mTORC1 inhibition activates the MAPK pathway through a PI3K-dependent feedback loop (a resistance mechanism)

In the Atlas

Links in the pathway map

Supports mTORC1 inhibits ERK / RSK (MAPK)

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Cite this paper

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Carracedo, A., Ma, L., Teruya-Feldstein, J., Rojo, F., Salmena, L., Alimonti, A., Egia, A., Sasaki, A. T., Thomas, G., Kozma, S. C., Papa, A., Nardella, C., Cantley, L. C., Baselga, J., & Pandolfi, P. P. (2008). Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. The Journal of clinical investigation. https://doi.org/10.1172/JCI34739

@article{CAR2008,
  author       = {Carracedo, A. and Ma, L. and Teruya-Feldstein, J. and Rojo, F. and Salmena, L. and Alimonti, A. and Egia, A. and Sasaki, A. T. and Thomas, G. and Kozma, S. C. and Papa, A. and Nardella, C. and Cantley, L. C. and Baselga, J. and Pandolfi, P. P.},
  title        = {{Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer}},
  journal      = {The Journal of clinical investigation},
  year         = {2008},
  doi          = {10.1172/JCI34739},
  note         = {PMID: 18725988},
}

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 CAR2008) [Data set]. https://mtor-atlas.org/study/CAR2008/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_CAR2008,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record CAR2008},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/CAR2008/},
  doi          = {10.5281/zenodo.22059963}
}

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