Isoform Switching as a Mechanism of Acquired Resistance to Mutant Isocitrate Dehydrogenase Inhibition

Harding, James J.; Lowery, Maeve A.; Shih, Alan H.; Schvartzman, Juan M.; Hou, Shengqi; Famulare, Christopher; Patel, Minal; Roshal, Mikhail; Gian, Richard Kinh; Zehir, Ahmet; You, Daoqi; Selcuklu, S. Duygu; Viale, Agnès; Tallman, Martin S.; Hyman, David M.; Reznik, Ed; Finley, Lydia W.S.; Papaemmanuil, Elli; Tosolini, Alessandra; Frattini, Mark G.; MacBeth, Kyle J.; Li, Xinwei; Fan, Bin; Choe, Sung; Wu, Bin; Janjigian, Yelena Y.; Mellinghoff, Ingo K.; Díaz, Luis A.; Levine, Ross L.; Abou‐Alfa, Ghassan K.; Stein, Eytan M.; Intlekofer, Andrew M.

doi:10.1158/2159-8290.cd-18-0877

Cited by 155 publications

(146 citation statements)

References 25 publications

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“…In 2008 and 2009, mutations in genes encoding IDH1 and IDH2 were identified in the patients with glioblastoma and acute myeloid leukemia [53][54][55]. To date, IDH mutations have been reported in a variety of cancers, such as angioimmunoblastic T-cell lymphoma, myelodysplastic syndromes, myeloproliferative neoplasms, cholangiocarcinoma, and chondrosarcoma 56,57. Mutant IDHs lose their initial catalytic function for the conversion of isocitrate to α-KG, and gain the function for the production of 2-hydroxyglutarate (2HG) from α-KG and NADPH.…”

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confidence: 99%

Hypoxia/pseudohypoxia‐mediated activation of hypoxia‐inducible factor‐1α in cancer

et al. 2019

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Since the first identification of hypoxic cells in sections of carcinomas in the 1950s, hypoxia has been known as a central hallmark of cancer cells and their microenvironment. Indeed, hypoxia benefits cancer cells in their growth, survival, and metastasis. The historical discovery of hypoxia‐inducible factor‐1α ( HIF 1A) in the early 1990s had a great influence on the field as many phenomena in hypoxia could be explained by HIF 1A. However, not all regions or types of tumors are necessarily hypoxic. Thus, it is difficult to explain whole cancer pathobiology by hypoxia, especially in the early stage of cancer. Upregulation of glucose metabolism in cancer cells has been well known. Oxygen‐independent glycolysis is activated in cancer cells even in the normoxia condition, which is known as the Warburg effect. Accumulating evidence and recent advances in cancer metabolism research suggest that hypoxia‐independent mechanisms for HIF signaling activation is a hallmark for cancer. There are various mechanisms that generate pseudohypoxic conditions, even in normoxia. Given the importance of HIF 1A for cancer pathobiology, the pseudohypoxia concept could shed light on the longstanding mystery of the Warburg effect and accelerate better understanding of the diverse phenomena seen in a variety of cancers.

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confidence: 99%

Hypoxia/pseudohypoxia‐mediated activation of hypoxia‐inducible factor‐1α in cancer

et al. 2019

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“…Moreover, the progression of standard chemotherapy was associated with decreasing serum levels of 2HG, supporting a prognostic potential of 2HG (16). The ability of mutant-IDH1 inhibitors to provide effects in AML having mutant-IDH2 stems from the ability to switch their mutagenesis toward unmutated IDH1, which turns to be the right target (63,69).…”

Section: Hg As An Oncometabolitementioning

confidence: 94%

“…A specific IDH2 inhibitor was developed to bind to the IDH2 dimer interface (179). Surprisingly, tumors targeted by the specific IDH1 inhibitors have the ability to switch their mutagenesis toward unmutated IDH2, which is not affected, and vice versa (63,69).…”

Section: Fig 1 Typical Cancer Metabolism Related To the Formation Omentioning

confidence: 99%

2-Hydroxyglutarate in Cancer Cells

Ježek

2020

Antioxidants & Redox Signaling

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Significance: Cancer cells are stabilized in an undifferentiated state similar to stem cells. This leads to profound modifications of their metabolism, which further modifies their genetics and epigenetics as malignancy progresses. Specific metabolites and enzymes may serve as clinical markers of cancer progression. Recent Advances: Both 2-hydroxyglutarate (2HG) enantiomers are associated with reprogrammed metabolism, in grade III/IV glioma, glioblastoma, and acute myeloid leukemia cells, and numerous other cancer types, while acting also in the cross talk of tumors with immune cells. 2HG contributes to specific alternations in cancer metabolism and developed oxidative stress, while also inducing decisions on the differentiation of naive T lymphocytes, and serves as a signal messenger in immune cells. Moreover, 2HG inhibits chromatin-modifying enzymes, namely 2-oxoglutarate-dependent dioxygenases, and interferes with hypoxia-inducible factor (HIF) transcriptome reprogramming and mammalian target of rapamycin (mTOR) pathway, thus dysregulating gene expression and further promoting cancerogenesis. Critical Issues: Typically, heterozygous mutations within the active sites of isocitrate dehydrogenase isoform 1 (IDH1) R132H and mitochondrial isocitrate dehydrogenase isoform 2 (IDH2) R140Q provide cells with millimolar r-2-hydroxyglutarate (r-2HG) concentrations, whereas side activities of lactate and malate dehydrogenase form submillimolar s-2-hydroxyglutarate (s-2HG). However, even wild-type IDH1 and IDH2, notably under shifts toward reductive carboxylation glutaminolysis or changes in other enzymes, lead to ''intermediate'' 0.01-0.1 mM 2HG levels, for example, in breast carcinoma compared with 10-8 M in noncancer cells. Future Directions: Uncovering further molecular metabolism details specific for given cancer cell types and sequence-specific epigenetic alternations will lead to the design of diagnostic approaches, not only for predicting patients' prognosis or uncovering metastases and tumor remissions but also for early diagnostics. Antioxid. Redox Signal. 00, 000-000.

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“…They demonstrated that IDH1 mutant tumor cells were more sensitive to poly adenosine diphosphate ribose polymerase inhibitors, which provided new clues to a personalized treatment strategy. Harding et al . revealed isoform switching between mutant IDH1 and IDH2 as a mechanism involved in the acquired drug resistance to mutant IDH1/2 inhibitors by analyzing four patients.…”

Section: Applications Of Metabolomics In Clinical Pharmacologymentioning

confidence: 99%

“…They STATE of the ART demonstrated that IDH1 mutant tumor cells were more sensitive to poly adenosine diphosphate ribose polymerase inhibitors, which provided new clues to a personalized treatment strategy. Harding et al 73 revealed isoform switching between mutant IDH1 and IDH2 as a mechanism involved in the acquired drug resistance to mutant IDH1/2 inhibitors by analyzing four patients. By gene sequencing and 2-HG production monitoring, Intlekofer et al 74 showed the appearance of second-site IDH2 mutations in trans or formation of IDH dimer-interface mutations in cis might be another mechanism for the acquired drug resistance to mutant IDH inhibitors.…”

Section: Identification Of New Drug Targetsmentioning

confidence: 99%

Emerging Applications of Metabolomics in Clinical Pharmacology

Pang

Wang

2019

Clin Pharma and Therapeutics

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Metabolic disturbances have been associated with many human diseases, including cancer, diabetes, and cardiovascular disease. Metabolomics, a rapidly growing member of the –omics family, investigates cellular metabolism by quantifying metabolites on a large scale and provides a link between metabolic pathways and the upstream genome that governs them. With the advances in analytical technologies, metabolomics is becoming a powerful tool for identifying diagnostic biomarkers of diseases, elucidating the pathological mechanisms, discovering novel drug targets, predicting drug responses, interpreting the mechanisms of drug action, as well as enabling precision treatment of patients. In this review, we highlight the recent advances of technologies and methodologies in metabolomics and their applications to the field of clinical pharmacology. Recent publications from 2013 to 2018 are covered in the review, and current challenges and potential future directions in the field are also discussed.

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Isoform Switching as a Mechanism of Acquired Resistance to Mutant Isocitrate Dehydrogenase Inhibition

Cited by 155 publications

References 25 publications

Hypoxia/pseudohypoxia‐mediated activation of hypoxia‐inducible factor‐1α in cancer

Hypoxia/pseudohypoxia‐mediated activation of hypoxia‐inducible factor‐1α in cancer

2-Hydroxyglutarate in Cancer Cells

Emerging Applications of Metabolomics in Clinical Pharmacology

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