Clinical Implications of Isocitrate Dehydrogenase Mutations and Targeted Treatment of Acute Myeloid Leukemia with Mutant Isocitrate Dehydrogenase Inhibitors-Recent Advances, Challenges and Future Prospects

Abstract

Despite the better understanding of the molecular mechanisms contributing to the pathogenesis of acute myeloid leukemia (AML) and improved patient survival in recent years, AML therapy still remains a clinical challenge. For this reason, it is important to search for new therapies that will enable the achievement of remission. Recently, the Food and Drug Administration approved three mutant IDH (mIDH) inhibitors for the treatment of AML. However, the use of mIDH inhibitors in monotherapy usually leads to the development of resistance and the subsequent recurrence of the cancer, despite the initial effectiveness of the therapy. A complete understanding of the mechanisms by which IDH mutations influence the development of leukemia, as well as the processes that enable resistance to mIDH inhibitors, may significantly improve the efficacy of this therapy through the use of an appropriate synergistic approach. The aim of this literature review is to present the role of IDH1/IDH2 mutations in the pathogenesis of AML and the results of clinical trials using mIDH1/IDH2 inhibitors in AML and to discuss the challenges related to the use of mIDH1/IDH2 inhibitors in practice and future prospects related to the potential methods of overcoming resistance to these agents.

Keywords: acute myeloid leukemia; enasidenib; isocitrate dehydrogenase inhibitors; ivosidenib; targeted therapy.

Figure 1

Wild-type IDH1 and IDH2 catalyze the reaction of converting citrate to 2-oxoglutarate (2-OG). Physiologically, 2-OG, after penetrating the cell nucleus, is involved in the activation of dioxygenases, which play a role in the process of deoxyribonucleic acid (DNA) and histone demethylation. IDH1—isocitrate dehydrogenase 1, IDH2—isocitrate dehydrogenase 2, 2-OG—2-oxoglutarate, NADPH—nicotinamide adenine dinucleotide phosphate, TCA—tricarboxylic acid, CoA—coenzymeA, TET1/TET2—ten-eleven translocation 1/2, JmjC—Jumonji-C family, KDMs—histone lysine demethylases, DNA—deoxyribonucleic acid. Image created with biorender.com (accessed on 19 June 2024).

Figure 2

(a) AlkB plays a role in the repair of alkylated DNA by converting mutagenic 1-methyladenine/3-methylcytosine into normal A/C bases. One of the substrates necessary to carry out the reaction is 2-OG. (b) In cancer cells with an IDH mutation, 2-HG is produced instead of 2-OG in the reaction catalyzed by the mutant enzymes. (c) Due to 2-OG deficiency and an increased intracellular 2-HG concentration, which is an AlkB inhibitor, there is the accumulation of methylated damage in the DNA, which may ultimately lead to the formation of further mutations in the cancer cell. 2-OG—2-oxoglutarate, NADPH—nicotinamide adenine dinucleotide phosphate, IDH—isocitrate dehydrogenase, 2-HG—2-hydroxyglutarate, DNA—deoxyribonucleic acid. Image created with biorender.com (accessed on 19 June 2024).

Figure 3

(a) PROTAC is a bifunctional molecule consisting of a ligand of the POI and a ligand of an E3 ubiquitin ligase (E3). The POI ligand and the E3 ligand are connected via a linker. (b) Mechanism of action: (1) PROTAC molecules penetrate the cell membrane; (2) upon POI binding to the ligand, PROTAC recruits E3 for (3) POI polyubiquitination, which ultimately leads to (4a) POI degradation, and (4b) the PROTAC molecule itself is recycled. PROTAC—proteolysis targeting chimera, E3—E3 ubiquitin ligase, E2—ubiquitin-conjugating enzyme, Ub—ubiquitin, POI—protein of interest. Image created with biorender.com (accessed on 11 July 2024).