Top

31-10-2017 | Acute myeloid leukemia | Article

The role of mutant IDH1 and IDH2 inhibitors in the treatment of acute myeloid leukemia

Journal: Annals of Hematology

Authors: Samah Nassereddine, Coen J. Lap, Faysal Haroun, Imad Tabbara

Publisher: Springer Berlin Heidelberg

Abstract

For decades, researchers have looked into the pathophysiology of acute myeloid leukemia (AML). With the advances in molecular techniques, the two-hit hypothesis was replaced by a multi-hit model, which also emphasizes the importance of aberrant epigenetic regulation in the pathogenesis of AML. IDH1 and IDH2 are two isoforms of isocitrate dehydrogenase that perform crucial roles in cellular metabolism. Somatic mutations in either of these two genes impart a neomorphic enzymatic activity upon the encoded enzymes resulting in the ability to convert α-ketoglutarate (αKG) into the oncometabolite R2-hydroxyglutarate (R2-HG), which can competitively inhibit multiple αKG-dependent dioxygenases. Inhibition of various classes of αKG-dependent dioxygenases results in dramatic epigenetic changes in hematopoietic cells, which has been found to directly impair differentiation. In addition to a global dysregulation of gene expression, other mechanisms have been described through which R2-HG promotes leukemic transformation including the induction of B cell lymphoma 2 dependency and stimulation of the EglN family of prolyl 4-hydroxylases (EglN). Due to the fact that mutations in IDH1 and IDH2 are acquired early during AML clonal evolution as well as because these mutations tend to remain stable during AML progression, the pharmaceutical industry has prompted the development of specific mutant IDH enzyme inhibitors. More recently, the FDA approved the first mutant IDH2 inhibitor, enasidenib (AG-221), for patients with relapsed or refractory IDH2-mutated AML (RR-AML). This has brought a lot of excitement to researchers, clinicians, and patients, especially because the treatment of AML remains challenging and is still associated with a high mortality.

Gilliland DG, Griffin JD (2002) The roles of FLT3 in hematopoiesis and leukemia. Blood 1 100(5):1532–1542CrossRef

Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts D et al (2016) Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med 374(23):2209–2221CrossRefPubMedPubMedCentral

Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K et al (2009) Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med 361(11):1058–1066CrossRefPubMedPubMedCentral

The Cancer Genome Atlas Research Network (2013) Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 368(22):2059–2074CrossRefPubMedCentral

Shih AH, Abdel-Wahab O, Patel JP, Levine RL (2012) The role of mutations in epigenetic regulators in myeloid malignancies. Nat Rev Cancer 12(9):599–612CrossRefPubMed

Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P et al (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321(5897):1807–1812CrossRefPubMedPubMedCentral

Dang L, Yen K, Attar EC (2016) IDH mutations in cancer and progress towards development of targeted therapeutics. Ann Oncol 27(4):599–608CrossRefPubMed

Yen KE, Bittinger MA, Su SM, Fantin VR (2010) Cancer-associated IDH mutations: biomarkers and therapeutic opportunities. Oncogene 29(49):6409–6417CrossRefPubMed

Reitman ZJ, Yan H (2010) Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism. J Natl Cancer Inst 102(13):932–941CrossRefPubMedPubMedCentral

10.

Gorrini C, Harris IS, Mak TW (2013) Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov 12(12):931–947CrossRefPubMed

11.

Lee SM, Koh HJ, Park DC, Song BJ, Huh TL, Park JW (2002) Cytosolic NADP(+) dependent isocitrate dehydrogenase status modulates oxidative damage to cells. Free Radic Biol Med 32(11):1185–1196CrossRefPubMed

12.

Kosmider O, Gelsi-Boyer V, Slama L, Dreyfus F, Beyne-Rauzy O, Quesnel B et al (2010) Mutations of IDH1 and IDH2 genes in early and accelerated phases of myelodysplastic syndromes and MDS/myeloproliferative neoplasms. Leukemia 24(5):1094–1096CrossRefPubMed

13.

Zhao S, Lin Y, Xu W, Jiang W, Zha Z, Wang P et al (2009) Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1α. Science 324(5924):261–265CrossRefPubMedPubMedCentral

14.

Carmeliet P, Dor Y, Herbert JM, Fukumura D, Brusselmans K et al (1998) Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and angiogenesis. Nature 394(6692):485–490CrossRefPubMed

15.

Dang L, White DW, Gross S, Bennet BD, Bittinger MA, Driggers EM et al (2010) Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 465(7300):966CrossRefPubMedPubMedCentral

16.

Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennet BD, Coller HA et al (2010) The common feature of leukemia-associated mutations is a neomorphic enzymatic activity that converts a-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17(3):225–234CrossRefPubMedPubMedCentral

17.

Losman JA, Looper RE, Koivunen P, Lee S, Schneider RK (2013) (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science 339(6127):1621–1625CrossRefPubMed

18.

Chaturvedi A, Araujo Cruz MM, Jyotsana N, Sharma A, Goparaju R (2016) Enantiomer-specific and paracrine leukemogenecity of mutant IDH metabolite 2-hydroxyglutarate. Leukemia 30(8):1708–1715CrossRefPubMedPubMedCentral

19.

McKenney AS, Levine RL (2013) Isocitrate dehydrogenase mutations in leukemia. J Clin Invest 123(9):3672–3677CrossRefPubMedPubMedCentral

20.

Kats LM, Reschke M, Taulli R, Pozdnyakova O, Burgess K, Bhargava P et al (2014) Proto-oncogenic role of mutant IDH2 in leukemia initiation and maintenance. Cell Stem Cell 14(3):329–341CrossRefPubMedPubMedCentral

21.

Grassian AR, Parker SJ, Davidson SM, Divakaruni AS, Green CR (2014) IDH1 mutations alter citric acid cycle metabolism and increase dependence on oxidative mitochondrial metabolism. Cancer Res 74(12):3317–3331CrossRefPubMedPubMedCentral

22.

Oizel K, Gratas C, Nadaradjane A, Oliver L, Vallette FM (2015) D-2-hydroxyglutarate does not mimic all the IDH mutation effects, in particular the reduced etoposide-triggered apoptosis mediated by an alteration in mitochondrial NADH. Cell Death Dis 6(3):e1704CrossRefPubMedPubMedCentral

23.

Sasaki M, Knobb CB, Munger JC, Lind EF, Brenner D, Brustle A et al (2012) IDH1(R132H) mutation increases murine haematopoietic prognitors and alters epigenetics. Nature 488(7413):656–659CrossRefPubMedPubMedCentral

24.

Chen C, Liu Y, Lu C, Cross JR, Morris JP 4th et al (2013) Cancer-associated IDH2 mutants drive an acute myeloid leukemia that is susceptible to Brd4 inhibition. Genes Dev 27(18):1974–1985CrossRefPubMedPubMedCentral

25.

Chaturvedi A, Araujo Cruz MM, Jyotsama N, Sharma A, Yun H et al (2013) Mutant IDH1 promotes leukemogenesis in vivo and can be specifically targeted in human AML. Blood 122(16):2877–2887CrossRefPubMed

26.

Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH et al (2011) Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of a-ketoglutarate-dependent dioxygenases. Cancer Cell 19(1):17–30CrossRefPubMedPubMedCentral

27.

Dan Y, Xiong Y, Guan GL (2012) The mechanism of IDH mutations in tumorigenesis. Cell Res 22(7):1102–1104CrossRef

28.

Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A et al (2010) Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function and impairs hematopoietic differentiation. Cancer Cell 18(6):553–567CrossRefPubMedPubMedCentral

29.

Koivunen P, Lee S, Duncan CG, Lopez G, Lu G (2012) Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature 483(7390):484–488CrossRefPubMedPubMedCentral

30.

Appelhoff RJ, Tian YM, Raval RR, Turley H, Harris AL et al (2004) Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor. J Biol Chem 279(37):38458–38465CrossRefPubMed

31.

Chan SM, Thomas D, Corces-Zimmerman MR, Xavy S, Rastogi S et al (2015) Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia. Nat Med 21(2):178–184CrossRefPubMedPubMedCentral

32.

Caramazza D, Lasho TL, Finke CM, Gangat N, Dingli D, Knudson RA et al (2010) IDH mutations and trisomy 8 in myelodysplastic syndromes and acute myeloid leukemia. Leukemia 24(12):2120–2122CrossRefPubMed

33.

Pardanani A, Patnaik MM, Lasho TL, Mai M, Knudson RA, Finke C et al (2010) Recurrent IDH mutations in high-risk myelodysplastic syndrome or acute myeloid leukemia with isolated del(5q). Leukemia 24(7):1370–1372CrossRefPubMed

34.

Marcucci G, Maharry K, Wu YZ, Radmacher MD, MroZek K, Margeson D et al (2010) IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a cancer and leukemia group B study. J Clin Oncol 28(14):2348–2355CrossRefPubMedPubMedCentral

35.

Im AP, Sehgal AR, Carroll MP, Smithg BD, Tefferi A, Johnson DE et al (2014) DNMT3A and IDH mutations in acute myeloid leukemia and other myeloid malignancies: associations with prognosis and potential treatment strategies. Leukemia 28(9):1774–1783CrossRefPubMedPubMedCentral

36.

DiNardo CD, Ravandi F, Agresta S, Konopleva M, Takahanshi K, Khadia T et al (2015) Characteristics, clinical outcome, and prognostic significance of IDH mutations in AML. Am J Hematol 90(8):732–736CrossRefPubMedPubMedCentral

37.

Thol F, Weissinger EM, Krauter J, Wagner K, Damm F, Wichmann M et al (2010) IDH1 mutations in patients with myelodysplastic syndrome are associated with an unfavorable prognosis. Haematologica 95(10):1668–1674CrossRefPubMedPubMedCentral

38.

Corces-Zimmerman MR, Hong WJ, Weissman IL, Medeiros BC, Majeti R (2014) Preleukemic mutations in human acute myeloid leukemia affect epigenetic regulators and persists in remission. Proc Natl Acad Sci U S A 111(7):2548–2553CrossRefPubMedPubMedCentral

39.

Chou WC, Lei WC, Ko BS, Hou HA, Chen CY et al (2011) Prognostic impact and stability of isocitrate dehydrogenase 2 mutation in adult patients with acute myeloid leukemia. Leukemia 25(2):246–253CrossRefPubMed

40.

Lin CC, Hou HA, Chou WC, Kuo YY, Liu CY, Chen CY et al (2014) IDH mutations are closely associated with mutations of DNMT3A, ASXL1 and SRSF2 in patients with myelodysplastic syndromes and are stable during disease evolution. Am J Hematol 89(2):137–144CrossRefPubMed

41.

Wang F, Travins J, DeLaBarre B, Penard-Lacronique V, Schalm S, Hansen E et al (2013) Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science 340(6132):622–626CrossRefPubMed

42.

Kernytsky A, Wang F, Hansen E, Schalm S, Straley K, Gliser C et al (2015) IDH2 mutation-induced histone and DNA hypermethylation is progressively reversed by small-molecule inhibition. Blood 125(2):296–303CrossRefPubMedPubMedCentral

43.

Shafer D, Grant S (2016) Update on rational targeted therapy in AML. Blood Rev 30(4):275–283CrossRefPubMedPubMedCentral

44.

DiNardo C, de Botton S, Pollyea DA, Stein ME, Fathi AT, Roboz GJ, et al (2015) Molecular profiling and relationship with clinical response in patients with IDH1 mutation-positive hematologic malignancies receiving AG-120, a first-in-class potent inhibitor of mutant IDH1, in addition to data from the completed dose escalation portion of the phase 1 study. Blood 126: Abstract 1306

45.

Birendra KC, DiNardo CD (2016) Evidence for clinical differentiation and differentiation syndrome in patients with acute myeloid leukemia and IDH1 mutations treated with the targeted mutant IDH1 inhibitor, AG-120. Clin Lymphoma Myeloma Leuk 16(8):460–465CrossRefPubMedPubMedCentral

46.

Dinardo C, Stein EM, Altman JK, Collins R, Deangelo D, Fathi A, et al (2015) AG-221, an oral, selective, first-in-class, potent inhibitor of the IDH2 mutant enzyme, induced durable responses in a phase 1 study of IDH2 mutation-positive advanced hematologic malignancies. 20th Annual Meeting of the European Hematology Association 13; Abstract: P569

47.

Stein E, Dinardo C, Altman J, Collins R, Deangelo D, Kantarjian H, et al (2015) Safety and efficacy of AG-221, a potent inhibitor of mutant IDH2 that promotes differentiation of myeloid cells in patients with advanced hematologic malignancies: results of a phase 1/2 trial. Blood 126(23S): Abstract 323

48.

Stein EM, Dinardo CD, Pollyea DA, Fathi AT, Roboz GJ et al (2017) Enasidenib in mutant-IDH2 relapsed or refractory acute myeloid leukemia. Blood 10 130(6):722–731CrossRef

49.

Chaturvedi A, Herbst L, Pusch S, Klett L, Goparaju R et al (2017) Pan-mutant-IDH1 inhibitor BAY1436032 is highly effective against human IDH1 mutant acute myeloid leukemia in vivo. Leukemia 24. https://doi.org/10.1038/leu.2017.46

50.

Pusch S, Kraussert S, Fischer V, Balss J, Ott M et al (2017) Pan-mutant IDH1 inhibitor BAY 1436032 for effective treatment of IDH1 mutant astrocytoma in vivo. Acta Neuropathol 133(4):629–644CrossRefPubMed

51.

DiNardo CD, Schimmer AD, Yee KW, Hochhaus A, Kraemer A, Carvajal RD, Janku F, et al (2016) A phase I study of IDH305 in patients with advanced malignancies including relapsed/refractory AML and MDS that harbor IDH1R132 mutations. Blood 128(22): Abstract 1073

Medicine Matters Oncology

Abstract