Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer
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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. RAD001 treatment also led to MAPK activation in a mouse model of prostate cancer. We further show that rapamycin-induced MAPK activation occurs in both normal cells and cancer cells lines and that this feedback loop depends on an S6K-PI3K-Ras pathway. Significantly, pharmacological inhibition of the MAPK pathway enhanced the antitumoral effect of mTORC1 inhibition by rapamycin in cancer cells in vitro and in a xenograft mouse model. Taken together, our findings identify MAPK activation as a consequence of mTORC1 inhibition and underscore the potential of a combined therapeutic approach with mTORC1 and MAPK inhibitors, currently employed as single agents in the clinic, for the treatment of human cancers.
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Inhibition of either PI3K/mTOR or ERK signaling often relieves feedback inhibition of the other and causes its activation.
“Inhibition of either PI3K/mTOR or ERK signaling often relieves feedback inhibition of the other and causes its activation46,47.”
From Combined inhibition of KRASG12C and mTORC1 kinase is synergistic in non-small cell lung cancer (2024) · cites this paper as [46]
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- Authors
- 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.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Memorial Sloan Kettering Cancer Center (US)
- Vall d'Hebron Hospital Universitari (ES)
- University of Cincinnati (US)
- Corresponding author
- Pandolfi, Pier Paolo
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2008-08-01
- Volume
- 118
- Issue
- 9
- Pages
- 3065-74
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC2518073
- OpenAlex
- W2157983986
- Cited by
- 1,381
- References
- 1
- Citations by year
- 2026: 23 · 2025: 26 · 2024: 25 · 2023: 42 · 2022: 40 · 2021: 48 · 2020: 55 · 2019: 63 · 2018: 73 · 2017: 98 · 2016: 111 · 2015: 122 · 2014: 114 · 2013: 129 · 2012: 118
- FWCI
- 40.36
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Iris (University of Trento) (submittedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
- Funders
- Pfizer
- Novartis
- Memorial Sloan-Kettering Cancer Center
- National Institutes of Health
- National Cancer Institute (U01CA084292, CA84292)
- National Institute of General Medical Sciences (R01GM041890)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- mTORC1 inhibition, MAPK pathway activation, phosphatidylinositol 3-kinase, S6K, Ras, feedback loops, rapamycin, everolimus, combination therapy, prostate cancer, solid tumors, anticancer activity
- MeSH terms
- Everolimus, Mechanistic Target of Rapamycin Complex 1, Animals, Antineoplastic Agents, Enzyme Activation, Enzyme Inhibitors, Humans, Immunosuppressive Agents, Neoplasms, Proteins, Transcription Factors, Gene Expression Regulation, Neoplastic, Sirolimus, MAP Kinase Signaling System, Feedback, Physiological, Cell Line, Tumor, Multiprotein Complexes, Mice, TOR Serine-Threonine Kinases
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