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===Therapeutic Implications===

===Therapeutic Implications===

Due to their reliance on oxidative phosphorylation ''IDH1''-mutated cancer cells are vulnerable to inhibitors of this metabolic process. The biguanides metformin and phenformin inhibit NADH dehydrogenase (complex I of the electron transport chain (ETC)), and ''IDH1'' mutations confer sensitivity to these agents[65]; metformin is currently undergoing clinical trial for use in patients with ''IDH1/2''-mutant solid tumours [66].  

Due to their reliance on oxidative phosphorylation ''IDH1''-mutated cancer cells are vulnerable to inhibitors of this metabolic process. The biguanides metformin and phenformin inhibit NADH dehydrogenase (complex I of the electron transport chain (ETC)), and ''IDH1'' mutations confer sensitivity to these agents [65]; metformin is currently undergoing clinical trial for use in patients with ''IDH1/2''-mutant solid tumors [66].  

''IDH1''-mutated cells also have a dependence on the glutaminolysis pathway. Although ''IDH1''-mutated cells need αKG to produce 2HG, they also restrict αKG production[5]. Producing αKG from glutamine allows for an alternative source of αKG in ''IDH''-mutated cells, but makes the cells vulnerable to inhibition of glutaminolysis with agents such as aminooxyacetic acid, BPTES, zaprinast, and chloroquinine in various cell types [67–70].  

''IDH1''-mutated cells also have a dependence on the glutaminolysis pathway. Although ''IDH1''-mutated cells need αKG to produce 2HG, they also restrict αKG production [5]. Producing αKG from glutamine allows for an alternative source of αKG in ''IDH''-mutated cells, but makes the cells vulnerable to inhibition of glutaminolysis with agents such as aminooxyacetic acid, BPTES, zaprinast, and chloroquinine in various cell types [67–70].  

''IDH1'' mutation disables the decarboxylation reaction that converts αKG to isocitrate, a reaction important in hypoxic conditions where pyruvate influx from the TCA cycle is compromised and cells must use citrate and acetyl-CoA generated from glutamine and glutamate in order to maintain the ability to synthesise lipids [71]. In primary glioblastoma, where ''IDH1'' is overexpressed, knockdown of ''IDH1'' sensitises glioma-initiating cells with EGFR amplifications to erlotinib through decreased fatty acid and cholesterol synthesis [72].

''IDH1'' mutation disables the decarboxylation reaction that converts αKG to isocitrate, a reaction important in hypoxic conditions where pyruvate influx from the TCA cycle is compromised and cells must use citrate and acetyl-CoA generated from glutamine and glutamate in order to maintain the ability to synthesize lipids [71]. In primary glioblastoma, where ''IDH1'' is overexpressed, knockdown of ''IDH1'' sensitizes glioma-initiating cells with ''EGFR'' amplifications to erlotinib through decreased fatty acid and cholesterol synthesis [72].

2HG inhibits cytochrome c oxidase (complex IV of the ETC), preventing cytochrome c release into the mitochondrial matrix. This makes IDH mutated cells vulnerable to apoptosis through BAX/BAK mediated permeabilisation of the outer mitochondrial membrane, although normally this is prevented by BCL-2 binding to the BAX/BAK proapoptotic proteins [43,44]. Disrupting BCL-2 binding with venetoclax, a BH3 mimetic, results in apoptosis of IDH mutated cells but unmutated cells are relatively insensitive [73]. This has been observed in AML patients and glioblastoma models, though in the latter case BCL-xL appeared to be the primary target of the BH3 mimetic rather than BCL-2 [44].

2HG inhibits cytochrome c oxidase (complex IV of the ETC), preventing cytochrome c release into the mitochondrial matrix. This makes ''IDH'' mutated cells vulnerable to apoptosis through BAX/BAK mediated permeabilisation of the outer mitochondrial membrane, although normally this is prevented by BCL-2 binding to the BAX/BAK proapoptotic proteins [43,44]. Disrupting BCL-2 binding with venetoclax, a BH3 mimetic, results in apoptosis of ''IDH'' mutated cells but unmutated cells are relatively insensitive [73]. This has been observed in AML patients and glioblastoma models, though in the latter case BCL-xL appeared to be the primary target of the BH3 mimetic rather than BCL-2 [44].

2HG downregulates nicotinate phosphoribosyltransferase (NAPRT1), which is an enzyme in the NAD+ salvage pathway. This leads to sensitivity to depletion of NAD+ in ''IDH1''-mutated cells by inhibition of nicotinamide phosphoribosyltransferase (NAMPT), another member of the pathway, with the preclinical compounds FK866 and GMX1778 leading to AMP kinase-initiated autophagy and cell death [45].

2HG downregulates nicotinate phosphoribosyltransferase (NAPRT1), which is an enzyme in the NAD+ salvage pathway. This leads to sensitivity to depletion of NAD+ in ''IDH1''-mutated cells by inhibition of nicotinamide phosphoribosyltransferase (NAMPT), another member of the pathway, with the preclinical compounds FK866 and GMX1778 leading to AMP kinase-initiated autophagy and cell death [45].

In AML, the ''IDH1'' Arg132His (NM_005896.2/NP_005887.2) mutant gene expression signature is indicative of a cellular phenotype that is responsive to treatment with small molecules targeting ROS and NAP+/NADPH signalling and metabolism [75].  

In AML, the ''IDH1'' Arg132His (NM_005896.2/NP_005887.2) mutant gene expression signature is indicative of a cellular phenotype that is responsive to treatment with small molecules targeting ROS and NAP+/NADPH signalling and metabolism [75].  

In pancreatic cancer cells, IDH1 has been linked to antioxidant defence as an adaptive strategy to cope with stress. Expression of ''IDH1'' is induced by HuR (Hu-Antigen R) after nutrient withdrawal or gemcitabine treatment. It has been suggested that this regulation is critical for pancreatic cancer cell survival under stress [76]. IDH1 mutations are rare in pancreatic cancer, however, probably owing to the importance of wild-type IDH1 function to pancreatic cancer cell survival.

In pancreatic cancer cells, ''IDH1'' has been linked to antioxidant defense as an adaptive strategy to cope with stress. Expression of ''IDH1'' is induced by HuR (Hu-Antigen R) after nutrient withdrawal or gemcitabine treatment. It has been suggested that this regulation is critical for pancreatic cancer cell survival under stress [76]. ''IDH1'' mutations are rare in pancreatic cancer, however, probably owing to the importance of wild-type IDH1 function to pancreatic cancer cell survival.

Mutant ''IDH1'' or ''IDH1'' knockdown radiosensitises cancerous and noncancerous cells[54,77], while ''IDH1'' overexpression is chemoprotective[78]. The radiosensitive phenotype of ''IDH1'' mutants is caused by both antioxidant depletion and impaired DNA damage response [54], the latter of which is associated with 2HG accumulation. The inhibition of ALKBH by 2HG also results in sensitisation of ''IDH1''-mutant cells to alkylating agents such as busulfan and CCNU [79], which provides an explanation for the sensitivity of ''IDH1''-mutated glioma to treatment with radiotherapy in the presence or absence of procarbazine, CCNU, and vincristine (the first two of which are alkylating agents) [80]. ''IDH1'' mutations also predict the response of glioblastoma to treatment with the DNA-alkylating agent temozolomide [81].

Mutant ''IDH1'' or ''IDH1'' knockdown radiosensitizes cancerous and noncancerous cells [54,77], while ''IDH1'' overexpression is chemoprotective [78]. The radiosensitive phenotype of ''IDH1'' mutants is caused by both antioxidant depletion and impaired DNA damage response [54], the latter of which is associated with 2HG accumulation. The inhibition of ALKBH by 2HG also results in sensitization of ''IDH1''-mutant cells to alkylating agents such as busulfan and CCNU [79], which provides an explanation for the sensitivity of ''IDH1''-mutated glioma to treatment with radiotherapy in the presence or absence of procarbazine, CCNU, and vincristine (the first two of which are alkylating agents) [80]. ''IDH1'' mutations also predict the response of glioblastoma to treatment with the DNA-alkylating agent temozolomide [81].

''IDH1''-mutated cancers are sensitive to PARP inhibitors, a phenotype that has been observed in AML and glioma [82,83], although the mechanism is unknown. Inhibition of the PARP-associated DNA repair pathway synergises with temozolomide in mutant glioma cells, and with daunorubicin in mutant AML, which suggests a treatment strategy that exploits the impaired DNA-repair pathway in ''IDH1''-mutants rather than using IDH1-mutant inhibitors may be beneficial [82]. In human cell models, a combination of ''IDH1'' mutation and ''ATM'' suppression caused sensitivity to irradiation and daunorubicin [82].

''IDH1''-mutated cancers are sensitive to PARP inhibitors, a phenotype that has been observed in AML and glioma [82,83], although the mechanism is unknown. Inhibition of the PARP-associated DNA repair pathway synergizes with temozolomide in mutant glioma cells, and with daunorubicin in mutant AML, which suggests a treatment strategy that exploits the impaired DNA-repair pathway in ''IDH1''-mutants rather than using ''IDH1''-mutant inhibitors may be beneficial [82]. In human cell models, a combination of ''IDH1'' mutation and ''ATM'' suppression caused sensitivity to irradiation and daunorubicin [82].

The fact that ''IDH1'' mutations arise very early in many cancers makes it an attractive therapeutic target, as the resulting tumour homogeneity decreases the risk of therapy resistance arising. IDH1-mutant inhibitors have been developed and show therapeutic promise in glioma, AML, and chondrosarcoma [84–87], although in AML these inhibitors may induce differentiation syndrome in some patients [88].

The fact that ''IDH1'' mutations arise very early in many cancers makes it an attractive therapeutic target, as the resulting tumor homogeneity decreases the risk of therapy resistance arising. ''IDH1''-mutant inhibitors have been developed and show therapeutic promise in glioma, AML, and chondrosarcoma [84–87], although in AML these inhibitors may induce differentiation syndrome in some patients [88].

==Common Alteration Types==

==Common Alteration Types==