Venetoclax and Hypomethylating Agent Combination in Myeloid Malignancies: Mechanisms of Synergy and Challenges of Resistance.
Rahul MishraMaedeh Zokaei NikooSindhusha VeeraballiAbhay SinghPublished in: International journal of molecular sciences (2023)
There has been a widespread adoption of hypomethylating agents (HMA: 5-Azacytidine (5-Aza)/decitabine) and venetoclax (Ven) for the treatment of acute myeloid leukemia (AML); however, the mechanisms behind the combination's synergy are poorly understood. Monotherapy often encounters resistance, leading to suboptimal outcomes; however, the combination of HMA and Ven has demonstrated substantial improvements in treatment responses. This study elucidates multiple synergistic pathways contributing to this enhanced therapeutic effect. Key mechanisms include HMA-mediated downregulation of anti-apoptotic proteins, notably MCL-1, and the priming of cells for Ven through the induction of genes encoding pro-apoptotic proteins such as Noxa. Moreover, Ven induces sensitization to HMA, induces overcoming resistance by inhibiting the DHODH enzyme, and disrupts antioxidant pathways (Nrf2) induced by HMA. The combination further disrupts oxidative phosphorylation in leukemia stem cells, amplifying the therapeutic impact. Remarkably, clinical studies have revealed a favorable response, particularly in patients harboring specific mutations, such as IDH1/2 , NPM1 , CEBPA , or ASXL1 . This prompts future studies to explore the nuanced underpinnings of these synergistic mechanisms in AML patients with these molecular signatures.
Keyphrases
- acute myeloid leukemia
- stem cells
- allogeneic hematopoietic stem cell transplantation
- anti inflammatory
- cell death
- oxidative stress
- newly diagnosed
- signaling pathway
- end stage renal disease
- combination therapy
- induced apoptosis
- cell proliferation
- ejection fraction
- genome wide
- randomized controlled trial
- type diabetes
- cancer therapy
- low grade
- cell cycle arrest
- prognostic factors
- dendritic cells
- gene expression
- immune response
- clinical trial
- single molecule
- weight loss
- cell therapy
- dna methylation
- drug delivery
- protein kinase
- single cell
- genome wide identification
- electronic health record