Antileukemic activity and mechanism of action of the novel PI3K and histone deacetylase dual inhibitor CUDC-907 in acute myeloid leukemia

Induction therapy for patients with acute myeloid leukemia has remained largely unchanged for over 40 years, while overall survival rates remain unacceptably low, highlighting the need for new therapies. The PI3K/Akt pathway is constitutively active in the majority of acute myeloid leukemia patients. Given that histone deacetylase inhibitors have been shown to synergize with PI3K inhibitors in preclinical acute myeloid leukemia models, we investigated the novel dual acting PI3K and histone deacetylase inhibitor CUDC-907 in acute myeloid leukemia cells both in vitro and in vivo. We demonstrate that CUDC-907 induces apoptosis in acute myeloid leukemia cell lines and primary patient samples and shows in vivo efficacy in an acute myeloid leukemia cell line-derived xenograft mouse model. CUDC-907-induced apoptosis was partially dependent on Mcl-1, Bim, and c-Myc. CUDC-907 induces DNA damage in acute myeloid leukemia cells while sparing normal hematopoietic cells. Downregulation of CHK1, Wee1, and RRM1, and induction of DNA damage also contributed to CUDC-907-induced apoptosis of acute myeloid leukemia cells. In addition, CUDC-907 treatment decreases leukemia progenitor cells in primary acute myeloid leukemia samples ex vivo, while also sparing normal hematopoietic progenitor cells. These findings support the clinical development of CUDC-907 for the treatment of acute myeloid leukemia.