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

Somatic mutations in isocitrate dehydrogenase 2 (IDH2) contribute to the pathogenesis of acute myeloid leukemia (AML) through production of the oncometabolite 2-hydroxyglutarate (2HG)(1–8). Enasidenib (AG-221) is an allosteric inhibitor that binds to the IDH2 dimer interface and blocks 2HG production by IDH2 mutants(9,10). In a phase I/II clinical trial, enasidenib inhibited 2HG production and induced clinical responses in relapsed/refractory IDH2-mutant AML(11). Here we describe two patients with IDH2-mutant AML who had a clinical response to enasidenib followed by clinical resistance, disease progression, and recurrent elevation in circulating 2HG. We found that therapeutic resistance was associated with the emergence of second-site IDH2 mutations in trans, such that 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 the IDH2 dimer. Expression of these mutant disease alleles alone did not induce 2HG production, however expression of Q316E and I319M mutations in concert with IDH2 R140Q in trans allowed for 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 elucidate a novel mechanism of acquired resistance to a targeted therapy and underscore the importance of 2HG production to the pathogenesis of IDH-mutant malignancies.