American Association for Cancer Research
Browse
21598290cd120404-sup-figs_9-11_1147k.pdf (1.12 MB)

Supplementary Figures 9-11 from The mTORC1 Inhibitor Everolimus Prevents and Treats Eμ-Myc Lymphoma by Restoring Oncogene-Induced Senescence

Download (1.12 MB)
journal contribution
posted on 2023-04-03, 20:21 authored by Meaghan Wall, Gretchen Poortinga, Kym L. Stanley, Ralph K. Lindemann, Michael Bots, Christopher J. Chan, Megan J. Bywater, Kathryn M. Kinross, Megan V. Astle, Kelly Waldeck, Katherine M. Hannan, Jake Shortt, Mark J. Smyth, Scott W. Lowe, Ross D. Hannan, Richard B. Pearson, Ricky W. Johnstone, Grant A. McArthur

PDF file - 1.1MB, Quantitation of SA-B-gal and immunostaining. SF10: Markers of senescence. SF11: Overall survival of mice transplanted with a p53 mutant lymphoma

History

ARTICLE 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. Cancer Discov; 3(1); 82–95. ©2012 AACR.This article is highlighted in the In This Issue feature, p. 1