Table of contents

1. Isocitrate dehydrogenase enzymes

2. IDHs Genetic Alterations

3. Wild-type IDHs in Cancer

4. IDH Inhibition in Cancer Enhances Responsiveness to Canonical Therapies

[This is a summary basedu on the review paper by Bergaggio E, Piva R, 2019]

1. Isocitiorate Dehydrogenase en

zymes

Isocitrate dehydrogenases (IDHs) are enzymes that catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (αKG), within the tricarboxylic acid (TCA) cycle. In humans, IDHs exist in three isoforms: IDH1, IDH2, and IDH3. Beyond their role in intermediary metabolism and energy production^[1][2] [1,2], IDH enzymes - which use either NAD+ or NADP+ as cofactors- are involved also in redox status regulation in a plethora of cellular functions^[3] [3]. Furthermore, αKG enables the activity of αKG-dependent dioxygenases required for essential processes, such as DNA and histone demethylation or DNA repair^[4][5] [4,5].

2. IDHs Genetic Alterations

IDHs enzymes have recently become of particular interest as mutations of IDH1 and IDH2 genes have been found in several malignancies and genetic diseases, such as gliomas^[6] [8], myeloid neoplasms^[7] [9], Ollier disease and Maffucci syndrome^[8] [10]. IDH1/2 mutant proteins display a new enzymatic activity able to catalyze the NADPH-dependent reduction of αKG, producing the oncometabolite D-2-hydroxyglutarate (D-2HG). This has a critical impact on the epigenetic cell status blocking cellular differentiation by competitively inhibiting αKG-dependent dioxygenases involved in histone and DNA demethylation, together with additional alterations in cellular metabolism, redox state and DNA repair^[9][10] [11,12].  These discoveries prompted the development of IDH1/2-mutant inhibitors such as enasidenib (AG-221), and ivosidenib (AG-120), approved by the FDA for the treatment of refractory or relapsed acute myeloid leukemia mutated in IDH2 or IDH1, respectively^[11][12] [13,14].

3. Wild-type IDHs in Cancer

Beyond IDHs mutations, aberrant expression of IDHs genes has also been related to carcinogenesis but its significance and their possible therapeutic implications remain to be further investigated. At present, it is not clear whether IDH1/2/3 activities may have a tumorigenic or tumor-suppressive role. While low expression of IDH1, IDH2, and IDH3 has been reported in several malignancies^[13][14] [15,16], their overexpression has been found to promote tumor growth and therapy resistance in other cancers^[15][16][17] [17

-19]. Overall, it emerges that the impact of IDH1/2/3 expression levels is strongly dependent on tumor type.

4. IDH Inhibition in Cancer Enhances Responsiveness to Canonical Therapies

Several lines of evidence suggest that IDH1/2/3 expression levels can be used as biomarkers for diagnosis, prognosis prediction, and target of therapy in specific neoplastic diseases. Additional studies also indicate that IDH1/2 inhibition could increase the efficacy of conventional cancer therapies, such as chemotherapy, radiotherapy, photodynamic therapy, and small molecule inhibitors^[15][18][19] [17,20

,21]

. The combination significantly decreases tricarboxylic acid cycle activity and ATP levels which exacerbate the damage caused by canonical therapies increasing cell death (Figure 1).  Importantly, this combinatorial effect occurs not only when IDH has an altered expression, but also when they are expressed at normal levels, increasing the applicability of IDH as potential targets for anticancer therapy. Since inhibitors directed against wild-type IDHs are not present on the market, further pre-clinical experiments could bring to the application of new drugs for IDH1/2 wild-type patients refractory to conventional therapy.

Figure 1. IDH inhibition enhances canonical cancer therapies efficacy. Schematic representation of the underlying mechanisms that increase the response to cancer therapies in presence of IDH1/2 inhibition.

References

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