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

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.

Resistance to the isocitrate dehydrogenase 1 mutant inhibitor ivosidenib can be overcome by alternative dimer-interface binding inhibitors

“…By contrast, the effects of the five inhibitors on cells over-producing R132C/S280F or R132H/S280F varied. Consistent with the biochemical data showing that the S280F substitution causes resistance to ivosidenib and prior clinical results 14 – 16 , ivosidenib was ineffective in suppressing 2-HG production in the R132C/S280F and R132H/S280F overproducing cells (Fig. 5 ).…”

“…2c ); these observations are consistent with prior work on IDH1 wt and R132H inhibition by ivosidenib 18 . It has been proposed, based on modelling studies 15 , 16 , that resistance to ivosidenib is mediated by hindrance to inhibitor binding due to substitution of S280 with a more sterically demanding phenylalanine (S280F), and that ivosidenib binding is additionally hindered by the loss of a hydrogen bond to the alcohol side chain of S280 16 . To investigate whether resistance is solely mediated by steric hindrance or other factors are involved, including those related to a potential loss of a hydrogen bond to S280, we produced R132C/S280A.…”

“…for acute myeloid leukaemia (AML) treatment where the cancer cells make an IDH variant 12 , 13 . However, ivosidenib resistance has emerged as a consequence of a second-site mutation that produces IDH1 R132C/S280F, with 5 cases having been reported to date 14 – 16 .…”

“…The precise mechanistic basis by which the second site IDH1 S280F substitution enables resistance to ivosidenib and its consequences for IDH1 variant inhibition beyond that for ivosidenib have been unclear 14 – 16 . We report biochemical, structural, and cellular studies on IDH1 R132C/S280F and IDH1 R132H/S280F that address these questions.…”

From Metabolism to Genetics and Vice Versa: The Rising Role of Oncometabolites in Cancer Development and Therapy

“…Other small IDH inhibitors such as olutasidenib (FT-2102) are currently under investigation in phase I/II clinical trials for AML and myelodysplastic syndrome [ 202 ] as well as vorasidenib (AG-881), a pan inhibitor of both IDH1/2 enzymes, has been evaluated in glioma (NCT04164901) [ 199 ]. Despite the promising results of these IDH inhibitors, some studies reported clinical cases of acquired resistance, which was found associated with the occurrence of a new second-site IDH2 mutations in trans or in cis at the level of the drug binding site [ 210 ], or with the emergence of an additional mutation that restored the R-2HG synthesis [ 211 ], while others exhibited the isoform switching phenomena from IDH1 to IDH2 and vice versa [ 212 ]. Moreover, the use of IDH inhibitors presents several challenges and their clinical application needs to be carefully evaluated.…”