title: The mTORC1 inhibitor everolimus prevents and treats Eμ-Myc lymphoma by restoring oncogene-induced senescence.
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.
  
  
  CONCLUSIONS
  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
authors.affiliation: Divisions of Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: Meaghan
authors.initials: M
authors.lastname: Wall
authors.forename: Gretchen
authors.initials: G
authors.lastname: Poortinga
authors.forename: Kym L
authors.initials: KL
authors.lastname: Stanley
authors.forename: Ralph K
authors.initials: RK
authors.lastname: Lindemann
authors.forename: Michael
authors.initials: M
authors.lastname: Bots
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Chan
authors.forename: Megan J
authors.initials: MJ
authors.lastname: Bywater
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Kinross
authors.forename: Megan V
authors.initials: MV
authors.lastname: Astle
authors.forename: Kelly
authors.initials: K
authors.lastname: Waldeck
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Hannan
authors.forename: Jake
authors.initials: J
authors.lastname: Shortt
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.forename: Scott W
authors.initials: SW
authors.lastname: Lowe
authors.forename: Ross D
authors.initials: RD
authors.lastname: Hannan
authors.forename: Richard B
authors.initials: RB
authors.lastname: Pearson
authors.forename: Ricky W
authors.initials: RW
authors.lastname: Johnstone
authors.forename: Grant A
authors.initials: GA
authors.lastname: McArthur
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000166:cytology / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects; D016922:Cellular Senescence; D000068338:Everolimus; D008223:Lymphoma / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008822:Mice, Transgenic; D046912:Multiprotein Complexes; D011506:Proteins / Q000037:antagonists & inhibitors*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases
chemical_list: D000970:Antineoplastic Agents; D046912:Multiprotein Complexes; D011506:Proteins; D016271:Proto-Oncogene Proteins c-myc; D000068338:Everolimus; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus