| First Author | Wall M | Year | 2013 |
| Journal | Cancer Discov | Volume | 3 |
| Issue | 1 | Pages | 82-95 |
| PubMed ID | 23242809 | Mgi Jnum | J:194369 |
| Mgi Id | MGI:5473485 | Doi | 10.1158/2159-8290.CD-12-0404 |
| Citation | Wall M, et al. (2013) The mTORC1 inhibitor everolimus prevents and treats Emu-Myc lymphoma by restoring oncogene-induced senescence. Cancer Discov 3(1):82-95 |
| abstractText | MYC deregulation is common in human cancer. IG-MYC translocations that are modeled in Emu-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 Emu-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 Emu-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 |
