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Ref Type Journal Article
PMID (36222845)
Authors Lyu J, Liu Y, Gong L, Chen M, Madanat YF, Zhang Y, Cai F, Gu Z, Cao H, Kaphle P, Kim YJ, Kalkan FN, Stephens H, Dickerson KE, Ni M, Chen W, Patel P, Mims AS, Borate U, Burd A, Cai SF, Yin CC, You MJ, Chung SS, Collins RH, DeBerardinis RJ, Liu X, Xu J
Title Disabling Uncompetitive Inhibition of Oncogenic IDH Mutations Drives Acquired Resistance.
Journal Vol Issue Date Pages Journal Short Title
Cancer discovery 13 1 2023 Jan 09 170-193 Cancer Discov
URL
Abstract Text Mutations in IDH genes occur frequently in acute myeloid leukemia (AML) and other human cancers to generate the oncometabolite R-2HG. Allosteric inhibition of mutant IDH suppresses R-2HG production in a subset of patients with AML; however, acquired resistance emerges as a new challenge, and the underlying mechanisms remain incompletely understood. Here we establish isogenic leukemia cells containing common IDH oncogenic mutations by CRISPR base editing. By mutational scanning of IDH single amino acid variants in base-edited cells, we describe a repertoire of IDH second-site mutations responsible for therapy resistance through disabling uncompetitive enzyme inhibition. Recurrent mutations at NADPH binding sites within IDH heterodimers act in cis or trans to prevent the formation of stable enzyme-inhibitor complexes, restore R-2HG production in the presence of inhibitors, and drive therapy resistance in IDH-mutant AML cells and patients. We therefore uncover a new class of pathogenic mutations and mechanisms for acquired resistance to targeted cancer therapies.Comprehensive scanning of IDH single amino acid variants in base-edited leukemia cells uncovers recurrent mutations conferring resistance to IDH inhibition through disabling NADPH-dependent uncompetitive inhibition. Together with targeted sequencing, structural, and functional studies, we identify a new class of pathogenic mutations and mechanisms for acquired resistance to IDH-targeting cancer therapies. This article is highlighted in the In This Issue feature, p. 1.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
IDH1 A410T missense no effect - predicted IDH1 A410T does not lie within any known functional domains of the Idh1 protein (UniProt.org). A410T does not lead to increased production of the oncometabolite 2HG (R(-)-2-hydroxyglutarate) in cell culture (PMID: 36222845), and therefore, is predicted to have no effect on Idh1 protein function.
IDH1 H315D missense no effect - predicted IDH1 H315D lies within an NADP-binding region of the Idh1 protein (UniProt.org). H315D confers resistance to an IDH1 inhibitor in the presence of IDH1 R132H, but does not lead to increased production of the oncometabolite 2HG (R(-)-2-hydroxyglutarate), and results in cytokine-independent growth and erythroid differentiation similar to wild-type protein in cell culture (PMID: 36222845), and therefore, is predicted to have no effect on Idh1 protein function. Y
IDH1 L409V missense no effect - predicted IDH1 L409V does not lie within any known functional domains of the Idh1 protein (UniProt.org). L409V does not lead to increased production of the oncometabolite 2HG (R(-)-2-hydroxyglutarate) in cell culture (PMID: 36222845), and therefore, is predicted to have no effect on Idh1 protein function.
IDH1 S280F missense no effect - predicted IDH1 S280F does not lie within any known functional domains of the Idh1 protein (UniProt.org). S280F confers resistance to an IDH1 inhibitor in the presence of IDH1 R132C/H (PMID: 29950729, PMID: 32380538, PMID: 36222845), but does not lead to increased production of the oncometabolite 2HG (R(-)-2-hydroxyglutarate) in cell culture (PMID: 36222845), and therefore, is predicted to have no effect on Idh1 protein function. Y
IDH1 T313I missense no effect - predicted IDH1 T313I lies within an NADP-binding region of the Idh1 protein (UniProt.org). T313I confers resistance to an IDH1 inhibitor in the presence of IDH1 R132H, but does not lead to increased production of the oncometabolite 2HG (R(-)-2-hydroxyglutarate), and results in cytokine-independent growth and erythroid differentiation similar to wild-type protein in cell culture (PMID: 36222845), and therefore, is predicted to have no effect on Idh1 protein function. Y
IDH2 A347T missense no effect - predicted IDH2 A347T does not lie within any known functional domains of the Idh2 protein (UniProt.org). A347T confers resistance to an IDH2 inhibitor in the presence of IDH2 R140Q, but does not lead to increased production of the oncometabolite 2HG (R(-)-2-hydroxyglutarate) in cell culture (PMID: 36222845), and therefore, is predicted to have no effect on Idh2 protein function. Y
IDH2 E343V missense no effect - predicted IDH2 E343V does not lie within any known functional domains of the Idh2 protein (UniProt.org). E343V confers resistance to an IDH2 inhibitor in the presence of IDH2 R140Q, but does not lead to increased production of the oncometabolite 2HG (R(-)-2-hydroxyglutarate) in cell culture (PMID: 36222845), and therefore, is predicted to have no effect on Idh2 protein function. Y
IDH2 E345G missense no effect - predicted IDH2 E345G does not lie within any known functional domains of the Idh2 protein (UniProt.org). E345G confers resistance to an IDH2 inhibitor in the presence of IDH2 R140Q, but does not lead to increased production of the oncometabolite 2HG (R(-)-2-hydroxyglutarate) in cell culture (PMID: 36222845), and therefore, is predicted to have no effect on Idh2 protein function. Y
IDH2 G450S missense no effect - predicted IDH2 G450S does not lie within any known functional domains of the Idh2 protein (UniProt.org). G450S does not lead to increased production of the oncometabolite 2HG (R(-)-2-hydroxyglutarate) in cell culture (PMID: 36222845), and therefore, is predicted to have no effect on Idh2 protein function.
IDH2 H348Q missense no effect - predicted IDH2 H348Q does not lie within any known functional domains of the Idh2 protein (UniProt.org). H348Q confers resistance to an IDH2 inhibitor in the presence of IDH2 R140Q, but does not lead to increased production of the oncometabolite 2HG (R(-)-2-hydroxyglutarate) in cell culture (PMID: 36222845), and therefore, is predicted to have no effect on Idh2 protein function. Y
IDH2 I319M missense no effect - predicted IDH2 I319M does not lie within any known functional domains of the Idh2 protein (UniPort.org). I319M confers resistance to an IDH2 inhibitor in the presence of IDH2 R140Q, but retains dimerization ability and does not lead to increased production of 2HG in culture (PMID: 29950729, PMID: 36222845), and therefore, is predicted to have no effect on Idh2 protein function. Y
IDH2 L449V missense no effect - predicted IDH2 L449V does not lie within any known functional domains of the Idh2 protein (UniProt.org). L449V does not lead to increased production of the oncometabolite 2HG (R(-)-2-hydroxyglutarate) in cell culture (PMID: 36222845), and therefore, is predicted to have no effect on Idh2 protein function.
IDH2 N136S missense no effect - predicted IDH2 N136S does not lie within any known functional domains of the Idh2 protein (UniProt.org). N136S confers resistance to an IDH2 inhibitor in the presence of IDH2 R140Q, but does not lead to increased production of the oncometabolite 2HG (R(-)-2-hydroxyglutarate) in cell culture (PMID: 36222845), and therefore, is predicted to have no effect on Idh2 protein function. Y
IDH2 Q316E missense no effect - predicted IDH2 Q316E does not lie within any known functional domains of the Idh2 protein (UniPort.org). Q316E confers resistance to an IDH2 inhibitor in the presence of IDH2 R140Q, but retains dimerization ability and does not lead to increased production of the oncometabolite 2HG (R(-)-2-hydroxyglutarate) in cell culture (PMID: 29950729, PMID: 36222845), and therefore, is predicted to have no effect on Idh2 protein function. Y
IDH2 R353H missense no effect - predicted IDH2 R353H does not lie within any known functional domains of the Idh2 protein (UniProt.org). R353H confers resistance to an IDH2 inhibitor in the presence of IDH2 R140Q, but does not lead to increased production of the oncometabolite 2HG (R(-)-2-hydroxyglutarate) in cell culture (PMID: 36222845), and therefore, is predicted to have no effect on Idh2 protein function. Y
IDH2 T352A missense no effect - predicted IDH2 T352A does not lie within any known functional domains of the Idh2 protein (UniProt.org). T352A confers resistance to an IDH2 inhibitor in the presence of IDH2 R140Q, but does not lead to increased production of the oncometabolite 2HG (R(-)-2-hydroxyglutarate) in cell culture (PMID: 36222845), and therefore, is predicted to have no effect on Idh2 protein function. Y
IDH2 V351I missense no effect - predicted IDH2 V351I does not lie within any known functional domains of the Idh2 protein (UniProt.org). V351I confers resistance to an IDH2 inhibitor in the presence of IDH2 R140Q, but does not lead to increased production of the oncometabolite 2HG (R(-)-2-hydroxyglutarate) in cell culture (PMID: 36222845), and therefore, is predicted to have no effect on Idh2 protein function. Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
IDH1 R132H IDH1 T313I leukemia predicted - resistant IDH305 Preclinical - Biochemical Actionable In a preclinical study, IDH305 did not inhibit R-2HG production in a leukemia cell line expressing IDH1 R132H and T313I in culture (PMID: 36222845). 36222845
IDH1 R132H IDH1 A410T leukemia predicted - sensitive Ivosidenib Preclinical - Biochemical Actionable In a preclinical study, Tibsovo (ivosidenib) inhibited enzymatic activity and R-2HG production in a leukemia cell line expressing IDH1 R132H and A410T in culture (PMID: 36222845). 36222845
IDH2 R140Q IDH2 G450S leukemia predicted - sensitive Enasidenib Preclinical - Biochemical Actionable In a preclinical study, Idhifa (enasidenib) inhibited enzymatic activity and R-2HG production in a leukemia cell line expressing IDH2 R140Q and G450S in culture (PMID: 36222845). 36222845
IDH1 R132H IDH1 S280F leukemia predicted - resistant Ivosidenib Preclinical - Biochemical Actionable In a preclinical study, Tibsovo (ivosidenib) did not inhibit Idh1 activity and R-2HG production in a leukemia cell line expressing IDH1 R132H and S280F in culture (PMID: 36222845). 36222845
IDH1 R132H IDH1 H315D leukemia predicted - resistant IDH305 Preclinical - Biochemical Actionable In a preclinical study, IDH305 did not inhibit R-2HG production in a leukemia cell line expressing IDH1 R132H and H315D in culture (PMID: 36222845). 36222845
IDH1 R132H IDH1 H315D leukemia predicted - resistant BAY1436032 Preclinical - Biochemical Actionable In a preclinical study, BAY1436032 did not inhibit R-2HG production in a leukemia cell line expressing IDH1 R132H and H315D in culture (PMID: 36222845). 36222845
IDH2 R140Q IDH2 E343V leukemia resistant Enasidenib Preclinical - Cell line xenograft Actionable In a preclinical study, a leukemia cell line expressing IDH2 R140Q and E343V was resistant to Idhifa (enasidenib) in culture and did not reduce tumor burden in a cell line xenograft model (PMID: 36222845). 36222845
IDH1 R132C IDH1 T313I acute myeloid leukemia predicted - resistant Ivosidenib Case Reports/Case Series Actionable In a clinical case study, IDH1 T313I was identified as an acquired mutation in a patient with acute myeloid leukemia harboring IDH1 R132C upon progression on Tibsovo (ivosidenib) (PMID: 36222845). 36222845
IDH2 R140Q IDH2 H348Q leukemia predicted - resistant Enasidenib Preclinical - Biochemical Actionable In a preclinical study, Idhifa (enasidenib) did not inhibit Idh2 activity and R-2HG production in a leukemia cell line expressing IDH2 R140Q and H348Q in culture (PMID: 36222845). 36222845
IDH2 R140Q IDH2 A347T leukemia predicted - resistant Vorasidenib Preclinical - Biochemical Actionable In a preclinical study, Vorasidenib (AG-881) did not inhibit R-2HG production in a leukemia cell line expressing IDH2 R140Q and A347T in culture (PMID: 36222845). 36222845
IDH2 R140Q IDH2 T352A leukemia predicted - resistant Enasidenib Preclinical - Biochemical Actionable In a preclinical study, Idhifa (enasidenib) did not inhibit Idh2 activity and R-2HG production in a leukemia cell line expressing IDH2 R140Q and T352A in culture (PMID: 36222845). 36222845
IDH2 R140Q IDH2 V351I acute myeloid leukemia predicted - resistant Enasidenib Case Reports/Case Series Actionable In a clinical case study, IDH2 V351I was identified as an acquired mutation in a patient with acute myeloid leukemia harboring IDH2 R140Q upon progression on Idhifa (enasidenib) (PMID: 36222845). 36222845
IDH1 R132H IDH1 T313I leukemia predicted - resistant Vorasidenib Preclinical - Biochemical Actionable In a preclinical study, Vorasidenib (AG-881) did not inhibit R-2HG production in a leukemia cell line expressing IDH1 R132H and T313I in culture (PMID: 36222845). 36222845
IDH2 R140Q IDH2 V351I leukemia predicted - resistant Enasidenib Preclinical - Biochemical Actionable In a preclinical study, Idhifa (enasidenib) did not inhibit Idh2 activity and R-2HG production in a leukemia cell line expressing IDH2 R140Q and V351I in culture (PMID: 36222845). 36222845
IDH2 R140Q IDH2 A347T leukemia resistant Enasidenib Preclinical - Cell line xenograft Actionable In a preclinical study, a leukemia cell line expressing IDH2 R140Q and A347T was resistant to Idhifa (enasidenib) in culture and did not reduce tumor burden in a cell line xenograft model (PMID: 36222845). 36222845
IDH2 R140Q IDH2 E343V leukemia predicted - resistant Vorasidenib Preclinical - Biochemical Actionable In a preclinical study, Vorasidenib (AG-881) did not inhibit R-2HG production in a leukemia cell line expressing IDH2 R140Q and E343V in culture (PMID: 36222845). 36222845
IDH2 R140Q IDH2 E345G leukemia predicted - resistant Enasidenib Preclinical - Biochemical Actionable In a preclinical study, Idhifa (enasidenib) did not inhibit Idh2 activity and R-2HG production in a leukemia cell line expressing IDH2 R140Q and E345G in culture (PMID: 36222845). 36222845
IDH2 R140Q IDH2 L449V leukemia predicted - sensitive Enasidenib Preclinical - Biochemical Actionable In a preclinical study, Idhifa (enasidenib) inhibited enzymatic activity and R-2HG production in a leukemia cell line expressing IDH2 R140Q and L449V in culture (PMID: 36222845). 36222845
IDH1 R132H IDH1 H315D leukemia resistant Ivosidenib Preclinical - Cell line xenograft Actionable In a preclinical study, Tibsovo (ivosidenib) did not inhibit Idh1 activity and R-2HG production in a leukemia cell line expressing IDH1 R132H and H315D in culture and did not reduce tumor burden in a cell line xenograft model (PMID: 36222845). 36222845
IDH1 R132H IDH1 T313I leukemia resistant Ivosidenib Preclinical - Cell line xenograft Actionable In a preclinical study, Tibsovo (ivosidenib) did not inhibit Idh1 activity and R-2HG production in a leukemia cell line expressing IDH1 R132H and T313I in culture and did not reduce tumor burden in a cell line xenograft model (PMID: 36222845). 36222845
IDH2 R140Q IDH2 E343V acute myeloid leukemia predicted - resistant Enasidenib Case Reports/Case Series Actionable In a clinical case study, IDH2 E343V was identified as an acquired mutation in a patient with acute myeloid leukemia harboring IDH2 R140Q upon progression on Idhifa (enasidenib) (PMID: 36222845). 36222845
IDH2 N136S IDH2 R140Q leukemia predicted - resistant Enasidenib Preclinical - Biochemical Actionable In a preclinical study, Idhifa (enasidenib) did not inhibit Idh2 activity and R-2HG production in a leukemia cell line expressing IDH2 R140Q and N136S in culture (PMID: 36222845). 36222845
IDH2 R140Q IDH2 Q316E leukemia predicted - resistant Enasidenib Preclinical - Biochemical Actionable In a preclinical study, Idhifa (enasidenib) did not inhibit Idh2 activity and R-2HG production in a leukemia cell line expressing IDH2 R140Q and Q316E in culture (PMID: 36222845). 36222845
IDH1 R132H IDH1 T313I leukemia predicted - resistant BAY1436032 Preclinical - Biochemical Actionable In a preclinical study, BAY1436032 did not inhibit R-2HG production in a leukemia cell line expressing IDH1 R132H and T313I in culture (PMID: 36222845). 36222845
IDH2 R140Q IDH2 I319M acute myeloid leukemia resistant Enasidenib Case Reports/Case Series Actionable In a clinical case study, IDH2 I319M was identified as an acquired mutation in a patient with acute myeloid leukemia harboring IDH2 R140Q upon progression on Idhifa (enasidenib) (PMID: 36222845). 36222845
IDH2 R140Q IDH2 I319M leukemia predicted - resistant Enasidenib Preclinical - Biochemical Actionable In a preclinical study, Idhifa (enasidenib) did not inhibit Idh2 activity and R-2HG production in a leukemia cell line expressing IDH2 R140Q and I319M in culture (PMID: 36222845). 36222845
IDH2 R140Q IDH2 R353H leukemia predicted - resistant Enasidenib Preclinical - Biochemical Actionable In a preclinical study, Idhifa (enasidenib) did not inhibit Idh2 activity and R-2HG production in a leukemia cell line expressing IDH2 R140Q and R353H in culture (PMID: 36222845). 36222845
IDH1 R132H IDH1 H315D leukemia predicted - resistant Vorasidenib Preclinical - Biochemical Actionable In a preclinical study, Vorasidenib (AG-881) did not inhibit R-2HG production in a leukemia cell line expressing IDH1 R132H and H315D in culture (PMID: 36222845). 36222845
IDH1 R132H IDH1 L409V leukemia predicted - sensitive Ivosidenib Preclinical - Biochemical Actionable In a preclinical study, Tibsovo (ivosidenib) inhibited enzymatic activity and R-2HG production in a leukemia cell line expressing IDH1 R132H and L409V in culture (PMID: 36222845). 36222845
IDH2 R140Q IDH2 A347T acute myeloid leukemia predicted - resistant Enasidenib Case Reports/Case Series Actionable In a clinical case study, IDH2 A347T was identified as an acquired mutation in a patient with acute myeloid leukemia harboring IDH2 R140Q upon progression on Idhifa (enasidenib) (PMID: 36222845). 36222845