title: Combined inhibition of PI3K-related DNA damage response kinases and mTORC1 induces apoptosis in MYC-driven B-cell lymphomas.
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 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.
authors: Gene Regulation Laboratory, Cancer Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, Australia.
authors: Jake
authors: J
authors: Shortt
authors: Benjamin P
authors: BP
authors: Martin
authors: Andrea
authors: A
authors: Newbold
authors: Katherine M
authors: KM
authors: Hannan
authors: Jennifer R
authors: JR
authors: Devlin
authors: Adele J
authors: AJ
authors: Baker
authors: Rachael
authors: R
authors: Ralli
authors: Carleen
authors: C
authors: Cullinane
authors: Clemens A
authors: CA
authors: Schmitt
authors: Maurice
authors: M
authors: Reimann
authors: Michael N
authors: MN
authors: Hall
authors: Meaghan
authors: M
authors: Wall
authors: Ross D
authors: RD
authors: Hannan
authors: Richard B
authors: RB
authors: Pearson
authors: Grant A
authors: GA
authors: McArthur
authors: Ricky W
authors: RW
authors: Johnstone
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002460:Cell Line; D004249:DNA Damage / Q000187:drug effects; D000070819:Discoidin Domain Receptor 1; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006657:Histones / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D011804:Quinolines / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016019:Survival Analysis; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000070819:Discoidin Domain Receptor 1; D006657:Histones; D007093:Imidazoles; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D016271:Proto-Oncogene Proteins c-myc; D011804:Quinolines; D020794:Receptor Protein-Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases; C092030:DDR1 protein, human; C531198:dactolisib; C475961:gamma-H2AX protein, mouse
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