Enhancing venetoclax activity in acute myeloid leukemia by co-targeting MCL1
T-C Teh, N-Y Nguyen, DM Moujalled, D Segal, G Pomilio, S Rijal, A Jabbour, K Cummins, K Lackovic, P Blombery, E Thompson, PG Ekert, G Lessene, SP Glaser, DCS Huang, AW Roberts, MA Guthridge, AH Wei
LEUKEMIA | NATURE PUBLISHING GROUP | Published : 2018
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 eff..View full abstract
Awarded by National Health and Medical Research Council
We thank Leukemia Foundation, Victorian Cancer Agency, Arrow Bone Marrow Transplant Foundation, Leukemia Lymphoma Society, Australian Cancer Research Foundation, Victorian State Government Operational Infrastructure Support (OIS) and the National Health and Medical Research Council (fellowships and grants including an Independent Infrastructure Support Scheme grant 9000220); we also thank Abbvie for providing venetoclax and A-1155463.