Dual Inhibition of Histone Deacetylases and Phosphoinositide 3-Kinase Enhances Therapeutic Activity Against B Cell Lymphoma

Oncogenic co-operation between c-Myc and activated phosphoinositide 3-kinase (PI3K) signaling pathways is crucial in lymphomagenesis, providing an opportunity for developing mechanism-based therapy to disrupt this co-operative survival mechanism. Combining constitutive c-Myc expression with constitutive PI3K activity in mouse germinal center B (GCB) cells resulted in Burkitt lymphoma-like tumors. Furthermore, analysis of primary human Burkitt lymphoma (BL) tissue sections revealed that two-thirds of the cases expressed high levels of phosphorylated AKT and S6 proteins, indicative of PI3K and mTORC1 activation. Prior attempts to develop small molecule inhibitors that specifically and directly target c-Myc protein have been unsuccessful. However, c-Myc cellular protein abundance can be decreased by using epigenetic modifying drugs (HDAC inhibitors or bromodomain/BET inhibitors) that are known to inhibit c-Myc transcription. Several investigators attempted disrupting c-Myc and PI3K cooperation by combining HDAC inhibitors and PI3K pathway inhibitors and synergic activity was demonstrated in DLBCL irrespective of subtype. In this study, we assessed the efficacy of CUDC-907, a new rationally designed dual inhibitor of PI3K and HDACs, in a panel of lymphoma cell lines. CUDC-907 treatment resulted in a dose- and time-dependent growth inhibition and cell death of DLBCL cell lines, irrespective of the cell of origin. CUDC-907 treatment down-regulated the phosphorylation of PI3K downstream targets, including AKT, PRAS40, S6, and 4EBP1, increased histone 3 acetylation, and decreased Myc protein levels. SILAC-based quantitative mass spectrometry demonstrated that CUDC-907 treatment decreased the protein levels of several components of the B cell receptor (BCR) and Toll like receptor (TLR) pathways, including BTK, SYK, and MyD88 proteins. These cellular changes were associated with an inhibition of NF-kB activation. CUDC-907 demonstrated in vivo efficacy with no significant toxicity in a human DLBCL xenograft mouse model. Collectively, these data provide a mechanistic rationale for evaluating CUDC-907 for the treatment of patients with c-Myc and PI3K-dependent lymphomas.