Journal article
Combined inhibition of PI3K-related DNA damage response kinases and mTORC1 induces apoptosis in MYC-driven B-cell lymphomas
J Shortt, BP Martin, A Newbold, KM Hannan, JR Devlin, AJ Baker, R Ralli, C Cullinane, CA Schmitt, M Reimann, MN Hall, M Wall, RD Hannan, RB Pearson, GA McArthur, RW Johnstone
Blood | Published : 2013
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 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 con..
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Funding Acknowledgements
J.S. was supported by funding from the Leukaemia Foundation of Australia and the Co-operative Research Centre for Biomedical Imaging Development. R.W.J. is a Principal Research Fellow of the National Health and Medical Research Council of Australia (NHMRC) and is supported by NHMRC Program and Project Grants, the Susan G. Komen Breast Cancer Foundation, Cancer Council Victoria, The Leukaemia Foundation of Australia, Victorian Breast Cancer Research Consortium, and the Victorian Cancer Agency. R. D. H. and R. B. P. are Senior Research Fellows of the NHMRC and are supported by NHMRC Project Grants and the Leukaemia Foundation of Australia.