The HDAC and PI3K dual inhibitor CUDC-907 synergistically enhances the antileukemic activity of venetoclax in preclinical models of acute myeloid leukemia.

In this study, we combine venetoclax with the dual PI3K and histone deacetylase inhibitor CUDC-907, which can downregulate Mcl-1, upregulate Bim, and induce DNA damage, as well as downregulate c-Myc. We establish that CUDC-907 and venetoclax synergistically induce apoptosis in acute myeloid leukemia cell lines and primary acute myeloid leukemia patient samples ex vivo. CUDC-907 downregulates CHK1, Wee1, RRM1, and c-Myc, which were found to play a role in venetoclax-induced apoptosis. Interestingly, we found that venetoclax treatment enhances CUDC-907-induced DNA damage potentially through inhibition of DNA repair. In vivo results show that CUDC-907 enhances venetoclax efficacy in an acute myeloid leukemia cell line derived xenograft mouse model, supporting the development of CUDC-907 in combination with venetoclax for the treatment of acute myeloid leukemia.
PMID: 32165486 [PubMed - as supplied by publisher]

Source: Haematologica - March 11, 2020 Category: Hematology Authors: Li X, Su Y, Hege K, Madlambayan G, Edwards H, Knight T, Polin L, Kushner J, Dzinic SH, White K, Yang J, Miller R, Wang G, Zhao L, Wang Y, Lin H, Taub JW, Ge Y Tags: Haematologica Source Type: research