PT - JOURNAL ARTICLE AU - Wall, Meaghan AU - Poortinga, Gretchen AU - Stanley, Kym L. AU - Lindemann, Ralph K. AU - Bots, Michael AU - Chan, Christopher J. AU - Bywater, Megan J. AU - Kinross, Kathryn M. AU - Astle, Megan V. AU - Waldeck, Kelly AU - Hannan, Katherine M. AU - Shortt, Jake AU - Smyth, Mark J. AU - Lowe, Scott W. AU - Hannan, Ross D. AU - Pearson, Richard B. AU - Johnstone, Ricky W. AU - McArthur, Grant A. TI - The mTORC1 Inhibitor Everolimus Prevents and Treats Eμ-<em>Myc</em> Lymphoma by Restoring Oncogene-Induced Senescence AID - 10.1158/2159-8290.CD-12-0404 DP - 2013 Jan 01 TA - Cancer Discovery PG - 82--95 VI - 3 IP - 1 4099 - http://cancerdiscovery.aacrjournals.org/content/3/1/82.short 4100 - http://cancerdiscovery.aacrjournals.org/content/3/1/82.full SO - CANCER DISCOVERY2013 Jan 01; 3 AB - 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. Cancer Discov; 3(1); 82–95. ©2012 AACR. This article is highlighted in the In This Issue feature, p. 1