Acquired resistance to IDH inhibition through trans or cis dimer-interface mutations

Abstract

Somatic mutations in the isocitrate dehydrogenase 2 gene (IDH2) contribute to the pathogenesis of acute myeloid leukaemia (AML) through the production of the oncometabolite 2-hydroxyglutarate (2HG). Enasidenib (AG-221) is an allosteric inhibitor that binds to the IDH2 dimer interface and blocks the production of 2HG by IDH2 mutants. In a phase I/II clinical trial, enasidenib inhibited the production of 2HG and induced clinical responses in relapsed or refractory IDH2-mutant AML. Here we describe two patients with IDH2-mutant AML who had a clinical response to enasidenib followed by clinical resistance, disease progression, and a recurrent increase in circulating levels of 2HG. We show that therapeutic resistance is associated with the emergence of second-site IDH2 mutations in trans, such that the resistance mutations occurred in the IDH2 allele without the neomorphic R140Q mutation. The in trans mutations occurred at glutamine 316 (Q316E) and isoleucine 319 (I319M), which are at the interface where enasidenib binds to the IDH2 dimer. The expression of either of these mutant disease alleles alone did not induce the production of 2HG; however, the expression of the Q316E or I319M mutation together with the R140Q mutation in trans allowed 2HG production that was resistant to inhibition by enasidenib. Biochemical studies predicted that resistance to allosteric IDH inhibitors could also occur via IDH dimer-interface mutations in cis, which was confirmed in a patient with acquired resistance to the IDH1 inhibitor ivosidenib (AG-120). Our observations uncover a mechanism of acquired resistance to a targeted therapy and underscore the importance of 2HG production in the pathogenesis of IDH-mutant malignancies.

An acidic residue buried in the dimer interface of isocitrate dehydrogenase 1 (IDH1) helps regulate catalysis and pH sensitivity

“…Interestingly, the D273 homolog in IDH2, D312, is located on the same side of the helix and only 5.3 Å from Q316 IDH2, a residue involved in acquired resistance to mutant IDH2 inhibitor binding. Q316E IDH1 has been identified in patients treated with the selective mutant IDH2 inhibitor Enasidenib (103), and results in resistance to this drug (104). Thus, our reported decrease in affinity for mutant IDH1 inhibitors is not surprising when considering the proximity of D273 to the allosteric pocket (Fig.…”

Pharmacological characterization of TQ05310, a potent inhibitor of isocitrate dehydrogenase 2 R140Q and R172K mutants

“…We found that the thermal-stabilizing effects of TQ05310 and AG-221 were lost in U-87 MG/IDH2-R140Q-Q316A cells, suggesting the critical role of the Q316 residue in binding these two inhibitors with IDH2-R140Q, and that the Q316 mutation may cause resistance to these inhibitors in patients with IDH2-R140Q. Notably, a study based on clinical observation reported that an AML patient with IDH2-R140Q showed an initial clinical response to AG-221, but developed drug resistance and disease progression after the emergence of the Q316E mutation in IDH2, 31 which confirmed the critical role of the Q316 residue in drug sensitivity. Collectively, these results indicate that monitoring Q316 mutations is important to predict the effectiveness of AG-221 and TQ05310 in patients harboring the IDH2-R140Q mutation.…”

New drugs creating new challenges in acute myeloid leukemia

“…Response to IDH inhibitors appears greater among patients with fewer concomitant mutations, which may explain the trend for higher response rates when patients are treated at earlier stages of disease. Interestingly, late relapses have been reported in association with rising 2‐HG and noncatalytic second site mutations located at the homodimer interface …”

“…Interestingly, late relapses have been reported in association with rising 2-HG and noncatalytic second site mutations located at the homodimer interface. 110 In the frontline AML setting, enasidenib produces CR/CRi of 21%-43% 111,112 and ivosidenib produces CR/CRh of 41%. 113 The median time to first response and CR to IDH inhibitors are approximately 1.9 months and 2.8 to 3.7 months, respectively, which can be challenging for patients with active disease needing to sustain therapy for several months without certainty of an eventual response.…”