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Figure 1. Schema of the molecular mechanisms of cotargeting IDH and methyltransferase in IDH mutant acute myeloid leukemia. The concurrently administered combination of the isocitrate dehydrogenase (IDH) inhibitor BAY1436032 (BAY) and the hypomethylating agent azacitidine (AZA) synergistically inhibits RAS/RAF/ERK1/2 and its downstream targets ELK1, ETS1, and CCND1 and blocks complex formation of CYCLIN D1/CDK4 to prevent RB phosphorylation, conse- quently inhibiting E2F release from the RB/E2F complex to promote cell cycle transition from G1 to S, leading to suppression of cell proliferation and self-renewal. In parallel, the combination of BAY and AZA upregulates the myeloid differentiation transcription factors PU.1, CEBPA, and GABPA to promote cell differentiation.
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inhibited proliferation in IDH mutant AML than in IDH wild-type AML. These data support the synergistic activi- ty of BAY1436032 and azacitidine and identify inhibition of the MAPK/RB pathways and activation of differentia- tion-related transcriptional factors as the key mechanisms underlying this synergism in IDH mutant AML.
Chaturvedi et al.’s1 work is important for several rea- sons. It is highly relevant to the ongoing clinical trials exploring combinations of IDH inhibitors and HMA, which have reported encouraging initial findings in patients with IDH mutant AML.13 These trials are designed to concurrently administer these agents, which was also confirmed in this study as being most efficacious. Furthermore, this work not only advances our under- standing of the molecular regulators affected by cotarget- ing IDH and methyltransferase, but also hints at the com- plexity of the inhibitory mechanisms that can be impacted by administration sequence and contribute to differential outcomes. The authors identified the MAPK/ERK- CYCLIN D1/CDK4-RB/E2F axis as critical to the regula- tion of LSC proliferation and the response to concurrent BAY1436032 and azacitidine. Whether this crosstalk between MAPK/ERK and RB/E2F signaling is intrinsic to IDH mutant AML, how it is associated with the terminal differentiation of LSC, and whether it can be utilized as a biomarker to predict outcomes are questions worthy of future exploration. Notably, despite its striking antileukemic activity in IDH mutant AML, the authors
indicated that concurrent BAY1436032 and azacitidine failed to completely eliminate LSC. Similarly, in ongoing trials, a small fraction of patients was primary refractory or experienced AML relapse while being treated with the combination regimen of IDH inhibitor and HMA. Hypotheses to explain treatment insensitivity include incomplete mutation clearance, polyclonal resistance, and/or clonal expansion associated with activation of mul- tiple kinases. Clearly, identification of the molecular deter- minants of primary and adaptive resistance is essential to refine the future therapeutic strategy. Given the genetic complexity and heterogeneity of AML, future large cohort studies and personalized molecular profiling at the single- cell level are needed to identify optimal therapeutic com- binations, aiming to achieve a curative response in AML patients carrying IDH mutations.
Disclosures
No conflicts of interest to disclose.
Contributions
ZZ and MK wrote and edited the manuscript.
References
1. Chaturvedi A, Gupta C, Gabdoulline R, et al. Synergistic activity of IDH1 inhibitor BAY1436032 with azacitidine in IDH1 mutant acute myeloid leukemia. Haematologica. 2020;106(2):565-573.
2.Waitkus MS, Diplas BH, Yan H. Biological role and therapeutic
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