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