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

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

doi:10.1158/2159-8290.CD-12-0404

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

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

Research output: Contribution to journal › Article › peer-review

62 Citations (Scopus)

Abstract

MYC deregulation is common in human cancer. IG-MYC translocations that are modeled in EμMyc 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 EμMyc 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 EμMyc 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.

Original language	English
Pages (from-to)	82-95
Number of pages	14
Journal	Cancer Discovery
Volume	3
Issue number	1
DOIs	https://doi.org/10.1158/2159-8290.CD-12-0404
Publication status	Published - Jan 2013
Externally published	Yes

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Wall, M., Poortinga, G., Stanley, K. L., Lindemann, R. K., Bots, M., Chan, C. J., Bywater, M. J., Kinross, K. M., Astle, M. V., Waldeck, K., Hannan, K. M., Shortt, J., Smyth, M. J., Lowe, S. W., Hannan, R. D., Pearson, R. B., Johnstone, R. W., & McArthur, G. A. (2013). The mTORC1 inhibitor everolimus prevents and treats Eμ-Myc lymphoma by restoring oncogene-induced senescence. Cancer Discovery, 3(1), 82-95. https://doi.org/10.1158/2159-8290.CD-12-0404

@article{67a6ce9d7a5e408488f3eb5ed4a7e108,

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 EμMyc 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 EμMyc 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 EμMyc 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.",

author = "Meaghan Wall and Gretchen Poortinga and Stanley, \{Kym L.\} and Lindemann, \{Ralph K.\} and Michael Bots and Chan, \{Christopher J.\} and Bywater, \{Megan J.\} and Kinross, \{Kathryn M.\} and Astle, \{Megan V.\} and Kelly Waldeck and Hannan, \{Katherine M.\} and Jake Shortt and Smyth, \{Mark J.\} and Lowe, \{Scott W.\} and Hannan, \{Ross D.\} and Pearson, \{Richard B.\} and Johnstone, \{Ricky W.\} and McArthur, \{Grant A.\}",

year = "2013",

month = jan,

doi = "10.1158/2159-8290.CD-12-0404",

language = "English",

volume = "3",

pages = "82--95",

journal = "Cancer Discovery",

issn = "2159-8274",

publisher = "American Association for Cancer Research Inc.",

number = "1",

}

Wall, M, Poortinga, G, Stanley, KL, Lindemann, RK, Bots, M, Chan, CJ, Bywater, MJ, Kinross, KM, Astle, MV, Waldeck, K, Hannan, KM, Shortt, J, Smyth, MJ, Lowe, SW, Hannan, RD, Pearson, RB, Johnstone, RW & McArthur, GA 2013, 'The mTORC1 inhibitor everolimus prevents and treats Eμ-Myc lymphoma by restoring oncogene-induced senescence', Cancer Discovery, vol. 3, no. 1, pp. 82-95. https://doi.org/10.1158/2159-8290.CD-12-0404

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T1 - The mTORC1 inhibitor everolimus prevents and treats Eμ-Myc lymphoma by restoring oncogene-induced senescence

AU - Wall, Meaghan

AU - Poortinga, Gretchen

AU - Stanley, Kym L.

AU - Lindemann, Ralph K.

AU - Bots, Michael

AU - Chan, Christopher J.

AU - Bywater, Megan J.

AU - Kinross, Kathryn M.

AU - Astle, Megan V.

AU - Waldeck, Kelly

AU - Hannan, Katherine M.

AU - Shortt, Jake

AU - Smyth, Mark J.

AU - Lowe, Scott W.

AU - Hannan, Ross D.

AU - Pearson, Richard B.

AU - Johnstone, Ricky W.

AU - McArthur, Grant A.

PY - 2013/1

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N2 - MYC deregulation is common in human cancer. IG-MYC translocations that are modeled in EμMyc 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 EμMyc 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 EμMyc 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.

AB - MYC deregulation is common in human cancer. IG-MYC translocations that are modeled in EμMyc 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 EμMyc 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 EμMyc 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.

UR - https://www.scopus.com/pages/publications/84872857051

U2 - 10.1158/2159-8290.CD-12-0404

DO - 10.1158/2159-8290.CD-12-0404

M3 - Article

SN - 2159-8274

VL - 3

SP - 82

EP - 95

JO - Cancer Discovery

JF - Cancer Discovery

IS - 1

ER -

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

Abstract

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