The mTORC1 inhibitor everolimus prevents and treats Eµ-Myc lymphoma by restoring oncogene-induced senescence.
Cancer Discov
; 3(1): 82-95, 2013 Jan.
Article
em En
| MEDLINE
| ID: mdl-23242809
ABSTRACT
UNLABELLED 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
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Base de dados:
MEDLINE
Assunto principal:
Proteínas
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Proteínas Proto-Oncogênicas c-myc
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Sirolimo
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Linfoma
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Antineoplásicos
Limite:
Animals
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article