Assessing acquired resistance to IDH1 inhibitor therapy by full-exon IDH1 sequencing and structural modeling
- Zoltán N. Oltvai1,2,3,4,7,
- Susan E. Harley1,5,7,
- David Koes2,
- Stephen Michel1,
- Erica D. Warlick6,
- Andrew C. Nelson1,
- Sophia Yohe1 and
- Pawel Mroz1
- 1Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota 55455, USA;
- 2Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA;
- 3Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA;
- 4Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, New York 14642, USA;
- 5Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, Minnesota 55455, USA;
- 6Department of Medicine, University of Minnesota, Minneapolis, Minnesota 55455, USA
- Corresponding author: pmroz{at}umn.edu
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↵7 These authors contributed equally to this work.
Abstract
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.
Footnotes
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[Supplemental material is available for this article.]
- Received November 8, 2020.
- Accepted January 26, 2021.
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