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EDITORIALS
Concurrent inhibition of IDH and methyltransferase maximizes therapeutic efficacy in IDH mutant acute myeloid leukemia
Zhihong Zeng1 and Marina Konopleva1,2
1Department of Leukemia, The University of Texas MD Anderson Cancer Center and 2Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
E-mail: MARINA KONOPLEVA - mkonople@mdanderson.org doi:10.3324/haematol.2020.266809
With findings of the molecular mechanisms of cotar- geting isocitrate dehydrogenase (IDH) and methyl- transferase with IDH inhibitors and a hypomethy- lating agent (HMA), Chaturvedi et al.1 provide new insights into combination therapy for IDH mutant acute myeloid leukemia (AML). Their manuscript entitled “Synergistic activity of IDH1 inhibitor BAY1436032 with azacitidine in IDH1 mutant acute myeloid leukemia,” published in this issue of Haematologica, reports that the concurrent adminis- tration of an IDH inhibitor and an HMA maximizes antileukemia efficacy in vitro and in vivo.
IDH is an enzyme that catalyzes conversion of isocitrate to α-ketoglutarate (α-KG); its metabolism plays an essential role in balancing cellular energy. IDH1 and IDH2 are 2 of the 3 iso- forms identified in humans; mutations in both isoforms are found in several malignancies, including AML. Mutant IDH1/2 converts α-KG to 2-hydroxyglutarate (2-HG), a metabolite structurally similar to α-KG, competitively inhibits α-KG–dependent enzymes, ultimately alters DNA and histone methylation, and impairs cellular growth and dif- ferentiation.2,3 Recurrent IDH1/2 mutations occur in up to 20% of patients with AML.4,5 In IDH mutant AML, overpro- duction of 2-HG leads to DNA and histone hypermethylation and myeloid cell differentiation arrest.6
Several small-molecule inhibitors of mutant IDH1 and IDH2 have been developed and are progressing through pre- clinical and clinical development.7,8 Two of them, ivosidenib and enasidenib, are approved by the Food and Drug Administration (FDA) for the treatment of newly diagnosed and relapsed/refractory IDH1 or IDH2 mutant AML, respec- tively. BAY1436032 is an oral, pan-mutant IDH1 inhibitor characterized by researchers in this study.9 BAY1436032 has shown strong antileukemic activity in two separate IDH1 mutant AML xenograft mouse models. This compound is cur- rently undergoing safety/efficacy testing in phase I dose esca- lation trials in patients with relapsed IDH1 mutant AML (clin- icaltrials gov. Indentifier: 03127735) and advanced solid tumors (clinicaltrials gov. Indentifier: 02746081).10 Despite high efficacy and on-target activity, IDH-targeted monother- apy in AML offers response rates of less than 50%. Resistance mechanisms, such as co-occurring mutations in receptor tyro- sine kinase signaling (FLT3, PTPN11, RAS, KIT), transcription factors (RUNX1, GATA2, CEBPA) and restoration of 2-HG through mutations in other IDH protein or IDH1 second site mutations, may account for the therapeutic failure; therefore, combination regimens are essential to improve clinical responses.11,12 The combination of an IDH1/2 inhibitor (ivosi- denib or enasidenib) with the HMA azacitidine is being eval- uated in an ongoing phase Ib/II study in patients with newly diagnosed IDH mutant AML who are ineligible for intensive chemotherapy (clinicaltrials gov. Indentifier: 02677922). This combination was well tolerated, with a safety profile consis- tent with that of ivosidenib or azacitidine monotherapy.
Clinical response rates exceeded those of azacitidine alone,
and importantly, most responders achieved IDH1 mutation
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clearance. Based on these findings, a phase III study of ivosi-
denib and azacitidine is actively enrolling patients (clinicaltri- als gov. Indentifier: 03173248). Despite these encouraging clinical responses, the molecular mechanisms of the interac- tion between IDH inhibitors and HMA are not well under- stood.
In this issue of Haematologica, Chaturvedi et al.1 investigated the efficacy and elucidated the mechanism of action of the novel IDH1 inhibitor BAY1436032 combined with azacitidine in both in vitro and in vivo preclinical models of IDH1 mutant AML. The authors observed that ex vivo treatment with BAY1436032 and azacitidine is more effective than single- agent treatment in its ability to induce the cell cycle S phase block, resulting in synergistic inhibition of colony formation in primary IDH1 mutant AML. Using two human IDH1 mutant AML xenograft models, the team evaluated the effi- cacy of BAY1436032 and azacitidine as single agents and in combination, with sequential (azacitidine followed by BAY1436032) or concurrent applications in vivo. Combination therapy induced differentiation and significantly prolonged survival compared to single agent or control cohorts. Importantly, concurrent administration of these agents, simi- lar to the design implemented in the ongoing clinical trials, produced the highest efficacy; this finding was further con- firmed in a secondary transplantation assay indicating that the concurrent combination therapy elicits the greatest reduc- tion in the number of leukemia stem cells (LSC).
Using transcriptomic (RNA sequencing) and epigenomic (DNA methylation arrays) analyses, the authors explored the mechanisms underlying this additive/synergistic efficacy, studying AML cells collected in vivo. Combination therapy decreased the expression of LSC gene sets and suppressed transcriptional factors in MAP kinase (RAS/RAF) and retinoblastoma/E2F (RB/E2F) pathways. Quantitative RT- PCR analysis confirmed that the cell survival/proliferation genes ELK1, ETS1, and CCND1 in the MAP kinase pathway and E2F1, CCNA2, and CCNE1 in RB/E2F signaling were additively suppressed, while the myeloid differentiation genes PU.1, CEBPA, and GABPA were upregulated in cells retrieved from the combination therapy arm. Using an IDH1- mutant fibrosarcoma cell line, the authors evaluated these findings at the translational level: the concurrently adminis- tered combination dephosphorylated ERK1/2 and downregu- lated the downstream targets of ELK1, ETS1 and CYCLIN D1. The lack of CYCLIN D1 limited CYCLIN D-CDK4 com- plex formation and consequently inhibited RB phosphoryla- tion on serine 795 and 807/811, thereby preventing RB from releasing E2F to regulate cell cycle G1 to S transition (Figure 1). Correspondingly, directly targeting the MAP kinase path- way with a MEK1/2 inhibitor, trametinib, or blocking the cell cycle with a CDK4/6 inhibitor, abemaciclib, more effectively
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haematologica | 2021; 106(2)