The mTORC1 inhibitor everolimus prevents and treats Eμ-Myc lymphoma by restoring oncogene-induced senescence

Wall, M., Poortinga, G., Stanley, K. L., Lindemann, R. K., Bots, M., Chan, C. J., Bywater, M. J., Kinross, K. M., Astle, M. V., Waldeck, K., Hannan, K. M., Shortt, J., Smyth, M. J., Lowe, S. W., Hannan, R. D., Pearson, R. B., Johnstone, R. W., McArthur, G. A. (January 2013) The mTORC1 inhibitor everolimus prevents and treats Eμ-Myc lymphoma by restoring oncogene-induced senescence. Cancer Discovery, 3 (1). pp. 82-95. ISSN 21598274

URL: http://www.ncbi.nlm.nih.gov/pubmed/23242809
DOI: 10.1158/2159-8290.CD-12-0404

Abstract

MYC deregulation is common in human cancer. IG-MYC translocations that are modeled in Eμ-Myc mice occur in almost all cases of Burkitt lymphoma as well as in other B-cell lymphoproliferative disorders. Deregulated expression of MYC results in increased mTOR complex 1 (mTORC1) signaling. As tumors with mTORC1 activation are sensitive to mTORC1 inhibition, we used everolimus, a potent and specific mTORC1 inhibitor, to test the requirement for mTORC1 in the initiation and maintenance of Eμ-Myc lymphoma. Everolimus selectively cleared premalignant B cells from the bone marrow and spleen, restored a normal pattern of B-cell differentiation, and strongly protected against lymphoma development. Established Eμ-Myc lymphoma also regressed after everolimus therapy. Therapeutic response correlated with a cellular senescence phenotype and induction of p53 activity. Therefore, mTORC1-dependent evasion of senescence is critical for cellular transformation and tumor maintenance by MYC in B lymphocytes. SIGNIFICANCE: This work provides novel insights into the requirements for MYC-induced oncogenesis by showing that mTORC1 activity is necessary to bypass senescence during transformation of B lymphocytes. Furthermore, tumor eradication through senescence elicited by targeted inhibition of mTORC1 identifies a previously uncharacterized mechanism responsible for significant anticancer activity of rapamycin analogues and serves as proof-of-concept that senescence can be harnessed for therapeutic benefit

Item Type: Paper
Subjects: diseases & disorders > cancer > cancer types > B cell lymphoma
diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > Myc
organs, tissues, organelles, cell types and functions > cell types and functions > cell functions
organs, tissues, organelles, cell types and functions > cell types and functions
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types
organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > senescence
diseases & disorders > cancer > cancer types
CSHL Authors:
Communities: CSHL labs > Lowe lab
Depositing User: Matt Covey
Date: January 2013
Date Deposited: 01 Apr 2013 14:31
Last Modified: 01 Apr 2013 14:31
PMCID: PMC3547521
Related URLs:
URI: http://repository.cshl.edu/id/eprint/28055

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