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 ( 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.
(© 2021 Oltvai et al.; Published by Cold Spring Harbor Laboratory Press.)