Enhancing venetoclax activity in acute myeloid leukemia by co-targeting MCL1

Teh, TC; Nguyen, NY; Moujalled, DM; Segal, D; Pomilio, G; Rijal, S; Jabbour, A; Cummins, K; Lackovic, K; Blombery, P; Thompson, E; Ekert, PG; Lessene, G; Glaser, SP; Huang, DCS; Roberts, AW; Guthridge, MA; Wei, AH

Author(s): Teh, TC; Nguyen, NY; Moujalled, DM; Segal, D; Pomilio, G; Rijal, S; Jabbour, A; Cummins, K; Lackovic, K; Blombery, P; Thompson, E; Ekert, PG; Lessene, G; Glaser, SP; Huang, DCS; Roberts, AW; Guthridge, MA; Wei, AH;
Details: Publication Year 2018-02,Volume 32,Issue #2,Page 303-312
Journal Title: Leukemia
Publication Type: Journal Article
Abstract: Targeted therapies are frequently combined with standard cytotoxic drugs to enhance clinical response. Targeting the B-cell lymphoma 2 (BCL-2) family of proteins is an attractive option to combat chemoresistance in leukemia. Preclinical and clinical studies indicate modest single-agent activity with selective BCL-2 inhibitors (for example, venetoclax). We show that venetoclax synergizes with cytarabine and idarubicin to increase antileukemic efficacy in a TP53-dependent manner. Although TP53 deficiency impaired sensitivity to combined venetoclax and chemotherapy, higher-dose idarubicin was able to suppress MCL1 and induce cell death independently of TP53. Consistent with an MCL1-specific effect, cell death from high-dose idarubicin was dependent on pro-apoptotic Bak. Combining higher-dose idarubicin with venetoclax was able to partially overcome resistance in Bak-deficient cells. Using inducible vectors and venetoclax to differentially target anti-apoptotic BCL-2 family members, BCL-2 and MCL1 emerged as critical and complementary proteins regulating cell survival in acute myeloid leukemia. Dual targeting of BCL-2 and MCL1, but not either alone, prolonged survival of leukemia-bearing mice. In conclusion, our findings support the further investigation of venetoclax in combination with standard chemotherapy, including intensified doses of idarubicin. Venetoclax should also be investigated in combination with direct inhibitors of MCL1 as a chemotherapy-free approach in the future.Leukemia advance online publication, 25 August 2017; doi:10.1038/leu.2017.243.
Publisher: Springer Nature
Research Division(s): Molecular Genetics Of Cancer; Cancer And Haematology; Chemical Biology
PubMed ID: 28751770
Publisher's Version: https://doi.org/10.1038/leu.2017.243
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2017-08-30 02:22:28

Last Modified: 2019-01-09 09:36:31