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Combined inhibition of PI3K-related DNA-damage response kinases and mTORC1 induces apoptosis in MYC-driven B-cell lymphomas

Item Type:Article
Title:Combined inhibition of PI3K-related DNA-damage response kinases and mTORC1 induces apoptosis in MYC-driven B-cell lymphomas
Creators Name:Shortt, J. and Martin, B.P. and Newbold, A. and Hannan, K.M. and Devlin, J.R. and Baker, A.J. and Ralli, R. and Cullinane, C. and Schmitt, C.A. and Reimann, M. and Hall, M.N. and Wall, M. and Hannan, R.D. and Pearson, R.B. and McArthur, G.A. and Johnstone, R.W.
Abstract:Pharmacological 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 multi-targeted pan-PI3K/dual-mTOR inhibitor, potently killed primary Myc-driven B-cell lymphomas and human cell lines bearing IG-cMYC translocations. Using pharmacological 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 pro-apoptotic 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 multi-targeted PI3K inhibitors in the treatment of hematological malignancies. In particular the newly elucidated role of PI3K-related DDR-kinases in the response to PI3K inhibitors offers a novel therapeutic opportunity for the treatment of hematological malignancies with a MYC-driven DDR.
Keywords:Apoptosis, B-Cell Lymphoma, Cell Line, Cultured Tumor Cells, DNA Damage, Drug Dose-Response Relationship, Flow Cytometry, Histones, Imidazoles, Inbred C57BL Mice, Knockout Mice, Multiprotein Complexes, Phosphatidylinositol 3-Kinases, Phosphorylation, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-myc, Quinolines, Receptor Protein-Tyrosine Kinases, Survival Analysis, TOR Serine-Threonine Kinases, Western Blotting, Animals, Mice
Publisher:American Society of Hematology
Page Range:2964-2974
Date:11 April 2013
Official Publication:https://doi.org/10.1182/blood-2012-08-446096
PubMed:View item in PubMed

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