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Ref Type Journal Article
PMID (33832922)
Authors Oltvai ZN, Harley SE, Koes D, Michel S, Warlick ED, Nelson AC, Yohe S, Mroz P
Title Assessing acquired resistance to IDH1 inhibitor therapy by full-exon IDH1 sequencing and structural modeling.
Journal Vol Issue Date Pages Journal Short Title
Cold Spring Harbor molecular case studies 7 2 2021 04 Cold Spring Harb Mol Case Stud
URL
Abstract Text Somatic mutations in hotspot regions of the cytosolic or mitochondrial isoforms of the isocitrate dehydrogenase gene (IDH1 and IDH2, respectively) contribute to the pathogenesis of acute myeloid leukemia (AML) by producing the oncometabolite 2-hydroxyglutarate (2-HG). The allosteric IDH1 inhibitor, ivosidenib, suppresses 2-HG production and induces clinical responses in relapsed/refractory IDH1-mutant AML. Herein, we describe a clinical case of AML in which we detected the neomorphic IDH1 p.R132C mutation in consecutive patient samples with a mutational hotspot targeted next-generation sequencing (NGS) assay. The patient had a clinical response to ivosidenib, followed by relapse and disease progression. Subsequent sequencing of the relapsed sample using a newly developed all-exon, hybrid-capture-based NGS panel identified an additional IDH1 p.S280F mutation known to cause renewed 2-HG production and drug resistance. Structural modeling confirmed that serine-to-phenylalanine substitution at this codon sterically hinders ivosidenib from binding to the mutant IDH1 dimer interface and predicted a similar effect on the pan-IDH inhibitor AG-881. Joint full-exon NGS and structural modeling enables monitoring IDH1 inhibitor-treated AML patients for acquired drug resistance and choosing follow-up therapy.

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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
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
IDH1 R132C IDH1 S280F acute myeloid leukemia predicted - resistant Ivosidenib Case Reports/Case Series Actionable In a clinical case study, a patient with acute myeloid leukemia (AML) harboring IDH1 R132C progressed following an initial response to treatment with Tibsovo (ivosidenib), and was found to have acquired IDH1 S280F (PMID: 33832922). 33832922