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

M Wall; G Poortinga; KL Stanley; RK Lindemann; M Bots; CJ Chan; MJ Bywater; KM Kinross; MV Astle; K Waldeck; KM Hannan; J Shortt; MJ Smyth; SW Lowe; RD Hannan; RB Pearson; RW Johnstone; GA McArthur

Journal article

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

M Wall, G Poortinga, KL Stanley, RK Lindemann, M Bots, CJ Chan, MJ Bywater, KM Kinross, MV Astle, K Waldeck, KM Hannan, J Shortt, MJ Smyth, SW Lowe, RD Hannan, RB Pearson, RW Johnstone, GA McArthur

Cancer Discovery | AMER ASSOC CANCER RESEARCH | Published : 2013

DOI: 10.1158/2159-8290.CD-12-0404

Abstract

MYC deregulation is common in human cancer. IG-MYC translocations that are modeled in EμMyc 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 EμMyc 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. Estab..

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University of Melbourne Researchers

Meaghan Wall Author

Gretchen Poortinga Author

Christopher Chan Author

Kelly Waldeck Author

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Awarded by National Cancer Institute

Funding Acknowledgements

R.W. Johnstone has a commercial research grant and has received honoraria for service on the speakers' bureau for Novartis. G. A. McArthur has commercial research grants from Novartis and Pfizer. No potential conflicts of interest were disclosed by the other authors. This work was supported by grants from the National Health and Medical Research Council of Australia to R. D. Hannan (166908 and 251688), R. B. Pearson (509087 and 400116), M.J. Smyth (454569), R.W. Johnstone (251608 and 566702), and G. A. McArthur (400120 and 566876) and from Cancer Council Victoria (to M. Wall, R. B. Pearson, and R. W. Johnstone), the Leukaemia Foundation of Australia (to C.J. Chan, R. W. Johnstone, and R. D. Hannan), the Victorian Cancer Agency (to M. Wall and R. W. Johnstone), the Susan G. Komen for the Cure Foundation (to R. W. Johnstone), the Australian Rotary Health Foundation (to R. W. Johnstone), and the National Cancer Institute (to S. W. Lowe). G. A. McArthur received the Sir Edward Dunlop Fellowship of the Cancer Council of Victoria.