Assessing acquired resistance to IDH1 inhibitor therapy by full-exon IDH1 sequencing and structural modeling

Somatic mutations in hotspot regions of the cytosolic or mitochondrial isoforms of the isocitrate dehydrogenase gene ( and , respectively) contribute to the pathogenesis of acute myeloid leukemia (AML) by producing the oncometabolite 2-hydroxyglutarate (2-HG). The allosteric IDH1 inhibitor, ivosiden...

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Bibliographic Details
Published in:Cold Spring Harbor molecular case studies 2021-04, Vol.7 (2), p.a006007
Main Authors: Oltvai, Zoltán N, Harley, Susan E, Koes, David, Michel, Stephen, Warlick, Erica D, Nelson, Andrew C, Yohe, Sophia, Mroz, Pawel
Format: Article
Language:English
Subjects:
Acute myeloid leukemia
Allosteric properties
Dimers
Drug resistance
Inhibitors
Isocitrate dehydrogenase
Isoforms
Leukemia
Mitochondria
Modelling
Mutants
Mutation
Myeloid leukemia
Next-generation sequencing
Pathogenesis
Phenylalanine
Research Report
Serine
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Summary:Somatic mutations in hotspot regions of the cytosolic or mitochondrial isoforms of the isocitrate dehydrogenase gene ( and , 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 -mutant AML. Herein, we describe a clinical case of AML in which we detected the neomorphic 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 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.
ISSN:2373-2865
2373-2873
DOI:10.1101/mcs.a006007