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

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.

LncRNA NEAT1 promotes dexamethasone resistance in multiple myeloma by targeting miR‐193a/MCL1 pathway

“…Elevated expression levels of MCL1 prevents cancer cells from initiating apoptosis in the face of many intrinsic tumor‐suppressing pathways and extrinsic therapeutic treatments aimed at controlling tumorigenesis . Recently, MCL1 has been a favorite target in treating NSCLC, human hepatocellular carcinoma, and acute myeloid leukemia . What is more, targeting MCL1 also constrained the growth of myeloma in vivo , which is pivotal for maintaining survival of most myelomas, and it should be prioritized for targeting in the clinic …”

BH3-Mimetic Drugs: Blazing the Trail for New Cancer Medicines

“…This suggested that the survival of AML cells was likely safeguarded by two or more pro-survival BCL-2 proteins. Pre-clinical studies confirmed the importance of MCL-1 as a key survival factor in AML (Glaser et al, 2012), supporting attempts to enhance venetoclax activity by adding chemotherapeutics that can indirectly neutralize MCL-1 (Bogenberger et al, 2014;Niu et al, 2016;Teh et al, 2018). Two parallel phase 1b/2 studies were developed to explore the potential of venetoclax in combination with either hypomethylating agents (HMA) or low-dose cytarabine (LDC) in elderly patients with AML unfit for intensive chemotherapy.…”

“…Clinical studies showed that the combination of venetoclax with HMA or LDC has reduced efficacy in patients with chemotherapy-relapsed or refractory AML (Aldoss et al, 2018;DiNardo et al, 2018b). An intriguing approach to enhance the activity of venetoclax in such resistant AML cases may involve directly targeting both BCL-2 and MCL-1, a strategy shown to be effective in pre-clinical AML model systems in vivo Moujalled et al, 2018;Ramsey et al, 2018;Teh et al, 2018). The emergence of potent MCL-1 inhibitors has made this feasible, and phase 1 clinical studies verifying the safety of S63845 and AMG 176 in humans are currently underway.…”

The Ibr‐7 derivative of ibrutinib exhibits enhanced cytotoxicity against non‐small cell lung cancer cells via targeting of mTORC1/S6 signaling

“…In previous studies, Mcl-1 was determined to be a critical anti-apoptotic factor controlling drug resistance in solid tumors, especially resistance to Bcl-2 inhibitors Souers et al, 2013;Zhang et al, 2016). The down-regulation of Mcl-1 could significantly enhance the antitumor effect of Bcl-2 inhibitors (Butterworth et al, 2016;Teh et al, 2018;Tong et al, 2017). In the Bcl-2 family, Bim, Puma and Noxa were reported to bind directly to Mcl-1 for proteasomal degradation (Chen et al, 2005;Delbridge et al, 2016).…”