CUDC‐907 blocks multiple pro‐survival signals and abrogates microenvironment protection in CLL

Abstract

CUDC‐907, a dual PI3K/HDAC inhibitor, has been proposed to have therapeutic potential in hematopoietic malignancies. However, the molecular mechanisms of its effects in chronic lymphocytic leukaemia (CLL) remain elusive. We show that CLL cells are sensitive to CUDC‐907, even under conditions similar to the protective microenvironment of proliferation centres. CUDC‐907 inhibited PI3K/AKT and HDAC activity, as expected, but also suppressed RAF/MEK/ERK and STAT3 signalling and reduced the expression of anti‐apoptotic BCL‐2 family proteins BCL‐2, BCL‐xL, and MCL‐1. Moreover, CUDC‐907 downregulated cytokines BAFF and APRIL and their receptors BAFFR, TACI, and BCMA, thus blocking BAFF‐induced NF‐κB signalling. T cell chemokines CCL3/4/17/22 and phosphorylation of CXCR4 were also reduced by CUDC‐907. These data indicated that CUDC‐907 abrogates different protective signals and suggested that it might sensitize CLL cells to other drugs. Indeed, combinations of low concentrations of CUDC‐907 with inhibitors of BCL2, BTK, or the NF‐κB pathway showed a potent synergistic effect. Our data indicate that, apart from its known functions, CUDC‐907 blocks multiple pro‐survival pathways to overcome microenvironment protection in CLL cells. This provides a rationale to evaluate the clinical relevance of CUDC‐907 in combination therapies with other targeted inhibitors.

High-throughput Screening with Pluripotent Stem Cells Identifies CUDC-907 as an Effective Compound for Restoring the Proinflammatory Phenotype of Nakajo-Nishimura Syndrome

“…CUDC-907 is a dual inhibitor of HDAC and PI3K-Akt [20]. It has also been reported to inhibit the growth of several tumor cells, including multiple myeloma and chronic lymphoma [36][37]. Based on those reports, CUDC-907 has been considered an anticancer drug.…”

“…This finding suggests that CUDC-907 could be applied to a variety of inflammatory disorders including NNS. However, given the tumor toxicity of CUDC-907 [36][37], its immediate clinical application to NNS patients is not realistic. Further evaluation of its effects and safety should be performed in the future.…”

Epigenetic polypharmacology: A new frontier for epi‐drug discovery

“…Thus, the pleiotropic effects induced by CUDC‐907 52 abrogate different protective and prosurvival signals, rescinding microenvironment protection and highlighting the possibility of sensitizing CLL cells to other drugs. Accordingly, a low concentration combination therapy based on CUDC‐907 52 and different inhibitors of NF‐κB (IMD‐0354), BTK (ibrutinib), and BCL2 (ABT‐199) signaling pathways lead to a potent synergistic effect . Different preclinical data in hematologic and solid cancer cell lines have shown that the effects obtained with CUDC‐907 52 in terms of tumor growth inhibition and multiple proapoptotic activities are more potent than those achieved using single PI3K or HDAC inhibitors.…”

Histone Deacetylase Inhibitors as Multitarget-Directed Epi-Drugs in Blocking PI3K Oncogenic Signaling: A Polypharmacology Approach

“…This concept has resulted in the design and development of multitarget epigenetic hybrid drugs. Among the several epigenetic hybrid drugs produced, CUDC-907 is a promising single dual HDAC-PI3K inhibitor molecule with an ability to simultaneously inhibit HDACs and PI3K [15,16,[134][135][136][137][138][139][140][141][142][143][144]. CUDC-907 is an orally bioavailable small -molecule dual HDAC and PI3K inhibitor targeting class I and II HDACs and PI3Kα, β, and δ isoforms [135].…”

“…CUDC-907 is an orally bioavailable small -molecule dual HDAC and PI3K inhibitor targeting class I and II HDACs and PI3Kα, β, and δ isoforms [135]. Its extensive antitumor activities in hematologic and solid tumors show promise as an HDAC-PI3K inhibitor [134][135][136][137][138][139][140][141][142][143][144]. Considering the pleiotropic effects of HDAC inhibition and the multiple downstream effectors of PI3K, it is not surprising CUDC-907 has a better opportunity to reverse the altered molecular pathways linked to oncogenesis.…”