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

Meaghan Wall, Gretchen Poortinga, Kym L Stanley, Ralph K Lindemann, Michael Bots, Christopher James Chan Chan, Megan Bywater, Kathryn M Kinross, Megan V Astle, Kelly Lee Waldeck, Katherine M Hannan, Jake Shortt, Mark J Smyth, Scott W Lowe, Ross Duncan Hannan, Richard Bruce Pearson, Ricky W Johnstone, Grant A McArthur

Research output: Contribution to journalArticleResearchpeer-review

50 Citations (Scopus)

Abstract

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
Original languageEnglish
Pages (from-to)82 - 95
Number of pages14
JournalCancer Discovery
Volume3
Issue number1
DOIs
Publication statusPublished - 2013

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