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

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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., 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. 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
Source:	Blood
ISSN:	0006-4971
Publisher:	American Society of Hematology
Volume:	121
Number:	15
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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