Inactivation of APC is a strongly predisposing event in the development of colorectal cancer1,2, prompting the search for vulnerabilities specific to cells that have lost APC function. Signalling through the mTOR pathway is known to be required for epithelial cell proliferation and tumour growth3,4,5, and the current paradigm suggests that a critical function of mTOR activity is to upregulate translational initiation through phosphorylation of 4EBP1 (refs 6, 7). This model predicts that the mTOR inhibitor rapamycin, which does not efficiently inhibit 4EBP1 (ref. 8), would be ineffective in limiting cancer progression in APC-deficient lesions. Here we show in mice that mTOR complex 1 (mTORC1) activity is absolutely required for the proliferation of Apc-deficient (but not wild-type) enterocytes, revealing an unexpected opportunity for therapeutic intervention. Although APC-deficient cells show the expected increases in protein synthesis, our study reveals that it is translation elongation, and not initiation, which is the rate-limiting component. Mechanistically, mTORC1-mediated inhibition of eEF2 kinase is required for the proliferation of APC-deficient cells. Importantly, treatment of established APC-deficient adenomas with rapamycin (which can target eEF2 through the mTORC1–S6K–eEF2K axis) causes tumour cells to undergo growth arrest and differentiation. Taken together, our data suggest that inhibition of translation elongation using existing, clinically approved drugs, such as the rapalogs, would provide clear therapeutic benefit for patients at high risk of developing colorectal cancer.

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W.J.F. is funded by AICR. O.J.S. is funded by Cancer Research UK, European Research Council Investigator Grant (COLONCAN) and the European Union Seventh Framework Programme FP7/2007-2013 under grant agreement number 278568. M.B. is a Medical Research Council Senior Fellow. The authors acknowledge P. Cammareri, J. Morton and C. Murgia for proofreading of the manuscript.

Author information

Author notes

    • Thomas J. Jackson
    •  & John R. P. Knight

    These authors contributed equally to this work.


  1. Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK

    • William J. Faller
    • , Rachel A. Ridgway
    • , Thomas Jamieson
    • , Saadia A. Karim
    • , Sorina Radulescu
    • , David J. Huels
    • , Kevin B. Myant
    • , Helen A. Casey
    • , Alessandro Scopelliti
    • , Julia B. Cordero
    • , Marcos Vidal
    •  & Owen J. Sansom
  2. Medical Research Council Toxicology Unit, Leicester LE1 9HN, UK

    • Thomas J. Jackson
    • , John R. P. Knight
    • , Carolyn Jones
    • , Kate M. Dudek
    • , Martin Bushell
    •  & Anne E. Willis
  3. Institut Necker-Enfants Malades, CS 61431, Paris, France Institut National de la Santé et de la Recherche Médicale, U1151, F-75014 Paris, France Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France

    • Mario Pende
  4. Department of Pharmacology, Rutgers The State University of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA

    • Alexey G. Ryazanov
  5. Department of Biochemistry and Goodman Cancer Research Center, McGill University, Montreal, Québec H3A 1A3, Canada

    • Nahum Sonenberg
  6. Department of Biochemistry and Molecular Biology, IMRIC, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel

    • Oded Meyuhas
  7. Biozentrum, University of Basel, CH-4056 Basel, Switzerland

    • Michael N. Hall


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O.J.S., A.E.W. and W.J.F. designed the project. W.J.F., R.A.R., T.J. and S.R. performed breeding and phenotypic analysis of mice; W.J.F., T.J.J. and J.R.P.K. performed translational analysis; M.N.H., A.G.R., N.S., O.M., A.S., J.B.C., M.V., D.J.H., K.B.M., S.A.K., K.M.D., C.J., H.A.C. and M.P. provided advice and material; W.J.F., O.J.S., A.E.W. and M.B. wrote and edited the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Owen J. Sansom.

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