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

Abstract

Key Points• MYC-driven lymphomas demonstrate activation of mTORC1 and an endogenous DNA damage response.• BEZ235 inhibits PI3K-related DNA damage response kinases and mTORC1, inducing p53-independent upregulation of proapoptotic BMF.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 IGcMYC 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. (Blood. 2013;121(15):2964-2974

Combination Therapy Targeting Ribosome Biogenesis and mRNA Translation Synergistically Extends Survival in MYC-Driven Lymphoma

“…PI3K-AKT-mTOR signaling modulates mRNA translation at both the initiation and elongation stages, including the promotion of eIF4E-dependent 5′ CAP-dependent translation initiation (20,21,23,25,26). We and others have previously demonstrated the vulnerability of MYC-driven B-lymphoma cells to a number of targeted therapeutic strategies that inhibit PI3K-AKT-mTOR signaling (18,20,(27)(28)(29)(30)(31). However, in all cases, disease relapse occurred despite continuing single-agent therapy.…”

“…38), including the proapoptotic BH3-only protein BCL2 modifying factor (BMF; refs. 29,39). In response to AKTi-1/2, KU-63794, BEZ235, and everolimus treatment, a robust increase in BMF protein abundance was detected in Eμ-Myc lymphoma cells (Fig.…”

“…Preclinical studies demonstrated that hematologic malignancies are particularly sensitive to CX-5461 (12,14), with CX-5461 progressing to phase I trials in patients with refractory blood cancers (ACTRN12613001061729). In addition, inhibitors of PI3K-AKT-mTOR signaling exhibit single-agent efficacy in mouse models of lymphoma and multiple myeloma (18,(27)(28)(29) and have been approved for treatment of hematologic malignancies, including the PI3Kδ inhibitor idelalisib for B-cell lymphoma and chronic lymphocytic leukemia (CLL) and the mTORC1 inhibitor temsirolimus for mantle cell lymphoma (43,49). Furthermore, this work has established the importance of Trp53 and Bmf for potent cooperation between everolimus and CX-5461 to treat MYC-driven lymphoma in vivo.…”

Glutaminolysis and autophagy in cancer

“…113,[136][137][138] The mechanism that explains this observation is related to the ability of MTORC1 to regulate the expression of FAN1/FANCD2, a protein involved in the activation of ATM. Thus, the inhibition of MTORC1 decreases FAN1, which impairs the activation of ATM and thereby the DDR of cancer cells.…”

Effects of NVP‑BEZ235, a dual phosphatidylinositol�3-kinase/mammalian target of rapamycin inhibitor, on HTLV-1-infected T-cell lines

“…Oral NVP-BEZ235 is reported to inhibit the kinase activities of mTORC1, mTORC2 and PI3K (15). Several pre-clinical studies reported the efficacy of NVP-BEZ235 in various lymphoid malignancies (14,(16)(17)(18) and its effects, either alone or in combination with other compounds, are currently being tested in the treatment of various other malignancies (12).…”