BRD4 inhibition sensitizes aggressive non-Hodgkin lymphomas to PI3Kδ inhibitors by suppressing PI3K reactivation and c-MYC expression

Targeting phosphatidylinositol 3-kinase 6 (PI3K6) is an important therapeutic strategy for indolent non Hodgkin lymphomas (NHLs). However, we previously observed reactivation of phosphatidylinositol 3-kinase (PI3K) pathways in aggressive NHL cell lines following continuous exposure to PI3K delta inhibitors (PI3K delta i), which limited their efficacy and suggests that more studies should be focused on this reactivation to improve current PI3K delta i-based treatments. Herein we conducted a drug synergy screening that combined a marketed PI3K delta i, idelalisib, with 14 well-characterized epigenetic drugs across several types of aggressive NHL cell lines. We identified BRD4 inhibitors (BRD4i) as potent partners that, in combination with idelalisib, were capable of synergistically exerting anti -proliferative activity and inducing cell apoptosis in a panel of aggressive NHL cell lines through continuous suppression of PI3K pathways. More importantly, the combination of BRD4i and PI3K delta i simultaneously inhibited transcription and translation of the oncogenic transcription factor c-MYC, downregulating the expression of c-MYC and continuously suppressing the proliferation of cancer cells in vitro, as well as the growth of tumors in vivo even after drug withdrawal. This study, thus, reveals the potential of simultaneously targeting PI3K delta and BRD4 as a new therapeutic strategy for aggressive forms of NHL.