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

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.