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dc.contributor.authorShortt, J
dc.contributor.authorMartin, BP
dc.contributor.authorNewbold, A
dc.contributor.authorHannan, KM
dc.contributor.authorDevlin, JR
dc.contributor.authorBaker, AJ
dc.contributor.authorRalli, R
dc.contributor.authorCullinane, C
dc.contributor.authorSchmitt, CA
dc.contributor.authorReimann, M
dc.contributor.authorHall, MN
dc.contributor.authorWall, M
dc.contributor.authorHannan, RD
dc.contributor.authorPearson, RB
dc.contributor.authorMcArthur, GA
dc.contributor.authorJohnstone, RW
dc.identifierpii: S0006-4971(20)49809-X
dc.identifier.citationShortt, J., Martin, B. P., Newbold, A., Hannan, K. M., Devlin, J. R., Baker, A. J., Ralli, R., Cullinane, C., Schmitt, C. A., Reimann, M., Hall, M. N., Wall, M., Hannan, R. D., Pearson, R. B., McArthur, G. A. & Johnstone, R. W. (2013). Combined inhibition of PI3K-related DNA damage response kinases and mTORC1 induces apoptosis in MYC-driven B-cell lymphomas. BLOOD, 121 (15), pp.2964-2974.
dc.descriptionC1 - Journal Articles Refereed
dc.description.abstractPharmacological strategies capable of directly targeting MYC are elusive. Previous studies have shown that MYC-driven lymphomagenesis is associated with mammalian target of rapamycin (mTOR) activation and a MYC-evoked DNA damage response (DDR) transduced by phosphatidylinositol-3-kinase (PI3K)-related kinases (DNA-PK, ATM, and ATR). Here we report that BEZ235, a multitargeted pan-PI3K/dual-mTOR inhibitor, potently killed primary Myc-driven B-cell lymphomas and human cell lines bearing IG-cMYC translocations. Using pharmacologic and genetic dissection of PI3K/mTOR signaling, dual DDR/mTORC1 inhibition was identified as a key mediator of apoptosis. Moreover, apoptosis was initiated at drug concentrations insufficient to antagonize PI3K/mTORC2-regulated AKT phosphorylation. p53-independent induction of the proapoptotic BH3-only protein BMF was identified as a mechanism by which dual DDR/mTORC1 inhibition caused lymphoma cell death. BEZ235 treatment induced apoptotic tumor regressions in vivo that correlated with suppression of mTORC1-regulated substrates and reduced H2AX phosphorylation and also with feedback phosphorylation of AKT. These mechanistic studies hold important implications for the use of multitargeted PI3K inhibitors in the treatment of hematologic malignancies. In particular, the newly elucidated role of PI3K-related DDR kinases in response to PI3K inhibitors offers a novel therapeutic opportunity for the treatment of hematologic malignancies with an MYC-driven DDR.
dc.subjectCancer Genetics; Cancer and Related Disorders
dc.titleCombined inhibition of PI3K-related DNA damage response kinases and mTORC1 induces apoptosis in MYC-driven B-cell lymphomas
dc.typeJournal Article
melbourne.peerreviewPeer Reviewed
melbourne.affiliationThe University of Melbourne
melbourne.affiliation.departmentThe Sir Peter Maccallum Department Of Oncology
melbourne.contributor.authorCullinane, Carleen
melbourne.contributor.authorHannan, Ross
melbourne.contributor.authorPearson, Richard
melbourne.contributor.authorMcArthur, Grant
melbourne.contributor.authorJohnstone, Ricky
melbourne.contributor.authorHannan, Katherine
melbourne.contributor.authorShortt, Jake
melbourne.contributor.authorNewbold, Andrea
melbourne.contributor.authorDEVLIN, JENNIFER
melbourne.contributor.authorMARTIN, BEN PAUL
melbourne.contributor.authorBaker, Adele
melbourne.fieldofresearch321103 Cancer genetics
melbourne.seocode200199 Clinical health not elsewhere classified
melbourne.accessrightsAccess this item via the Open Access location

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