Abstract
Phosphoinositide 3-kinase (PI3K) and Myc are known to cooperate in promoting the survival and growth of a variety of B-cell lymphomas. While currently there are no small molecule inhibitors of Myc protein, histone deacetylase (HDAC) inhibitors have been shown to reduce levels of Myc protein by suppressing its transcription. 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 Myc and PI3K-dependent lymphomas.
Highlights
There is clear evidence for the oncogenic cooperation between Myc and activated phosphoinositide 3-kinase (PI3K) signaling pathway in lymphomagenesis, providing an opportunity for developing mechanism-based therapy to disrupt this cooperative survival mechanism
Using Annexin V- propidium iodide staining, we found that CUDC907 induced cell death by apoptosis after 24 hrs at low concentration (0.1 μM) in three representative diffuse large B-cell lymphoma (DLBCL) cell lines, SUDHL-6 (GCB), HBL-1 (ABC) and NUDHL-1 (DHL), but was ineffective in the Hodgkin lymphoma (HL) cell line KMH-2 (Figure 1C)
The in vitro activity was confirmed in a human DLCBL xenograft model, whereas CUDC-907 was capable of inhibiting Phosphoinositide 3-kinase (PI3K) and histone deacetylase (HDAC) in vivo
Summary
There is clear evidence for the oncogenic cooperation between Myc and activated phosphoinositide 3-kinase (PI3K) signaling pathway in lymphomagenesis, providing an opportunity for developing mechanism-based therapy to disrupt this cooperative survival mechanism. Most published series reported about 10% of DLBCL harbored Myc, Bcl and/or Bcl translocations and predominantly seen in the subset of GCB subtype [7,8,9,10,11,12,13]. This category was called “double hit” lymphoma (DHL) or triple hit lymphoma and now is recognized as “high grade B-cell lymphoma (HGBL) with rearrangements of Myc and Bcl and/or Bcl6 [14]. Myc cellular protein abundance can be decreased by using epigenetic modifying drugs (HDAC inhibitors or bromodomain/BET inhibitors) that are known to inhibit Myc transcription [15, 16]
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