Isocitrate Dehydrogenase (IDH) Mutations

The isocitrate dehydrogenase (IDH) proteins are critical enzymes in the Krebs cycle, which is central to many biochemical pathways.1-3 IDH occurs in 3 isoforms: IDH1, IDH2, and IDH3.1,3 All IDH isoforms catalyze the conversion of isocitrate to α-ketoglutarate (α-KG)—but in different cellular compartments.3,4 IDH1 is found in the cytoplasm and peroxisomes, whereas IDH2 and IDH3 are found in the mitochondria.3,4  It is hypothesized that IDH1 and IDH2 mutations may initiate and drive cancer growth by blocking the differentiation of primitive cells.5,6 Cancer-associated IDH3 mutations have not been reported.

Acquiring a somatic mutation in either IDH1 or IDH2 can confer gain-of-function activity in cancer cells, which may result in accumulation of the oncometabolite 2-hydroxyglutarate (2-HG).5,6 In preclinical studies, cancer cells with mutated IDH1/2 have elevated 2-HG levels, resulting in an increase in the inhibition of DNA and histone demethylating enzymes that utilize α-KG, such as tet methylcytosine dioxygenase 2 (TET2) and lysine (K)-specific demethylase (KDM).7-9 Elevated 2-HG levels associated with mutant IDH1/2 can lead to global changes in DNA and histone methylation, impairment of cellular differentiation, and potential tumorogenesis.6-10 Preclinical studies suggest that inhibiting gain-of-function mutant IDH1/2 prevents the excess production of 2-HG and may restore cellular differentiation.9,11-13

Mutations to either IDH1 or IDH2 have been observed in multiple cancers, including acute myeloid leukemia (AML), grade II/III glioma and secondary glioblastoma, chondrosarcoma, intrahepatic cholangiocarcinoma, angioimmunoblastic T cell lymphoma, thyroid carcinoma, and myelodysplastic syndromes (MDS).14-16


2-HG, 2-hydroxyglutarate; α-KG, α-ketoglutarate; IDH, isocitrate dehydrogenase; KDM, lysine (K)-specific demethylase; TET2, tet methylcytosine dioxygenase 2.

The safety and efficacy of the agents and/or uses under investigation have not been established. There is no guarantee that the agents will receive health authority approval or become commercially available in any country for the uses being investigated.

References

  1. Reitman ZJ, Yan H. J Natl Cancer Inst. 2010;102:932-941.
  2. Raimundo N, et al. Trends Mol Med. 2011;17:641-649.
  3. Losman JA, Kaelin WG Jr. Genes Dev. 2013;27:836-852.
  4. Krell D, et al. Future Oncol. 2013;9:1923-1935.
  5. Ward PS, et al. Cancer Cell. 2010;17:225-234.
  6. Figueroa ME, et al. Cancer Cell. 2010;18:553-567.
  7. Cardaci S, Ciriolo MR. Int J Cell Biol. 2012;2012:161837.
  8. Krall AS, Christofk HR. Nature. 2013;496:38-40.
  9. Losman JA, et al. Science. 2013;339:1621-1625.
  10. Turcan S, et al. Nature. 2012;483:479-483.
  11. Rohle D, et al. Science. 2013;340:626-630.
  12. Kernytsky A, et al. Blood. 2015;125:296-303.
  13. Wang F, et al. Science. 2013;340:622-626.
  14. Cairns RA, Mak TW. Cancer Discov. 2013;3:730-741.
  15. Yang H, et al. Clin Cancer Res. 2012;18:5562-5571.
  16. Thol F, et al. Haematologica. 2010; 95:1668-1674