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
- end stage renal disease
- cell death
- oxidative stress
- combination therapy
- newly diagnosed
- genome wide
- peritoneal dialysis
- induced apoptosis
- signaling pathway
- prognostic factors
- immune response
- adipose tissue
- bone marrow
- metabolic syndrome
- chronic lymphocytic leukemia
- cell cycle arrest
- type diabetes
- dna methylation
- single molecule
- transcription factor
- skeletal muscle
- patient reported