Two patients with IDH2R140Q AML acquired resistance to an IDH2 inhibitor via secondary IDH2 mutations.
Major finding: Two patients with IDH2R140Q AML acquired resistance to an IDH2 inhibitor via secondary IDH2 mutations.
Concept: IDH2 Q316E or I319M mutations blocked enasidenib binding, cooperating with IDH2R140Q to reduce 2HG levels.
Impact: Acquired Q316E or I319M mutations may underlie enasidenib resistance in patients with IDH2R140Q AML.
Mutations in IDH2 result in production of the oncometabolite 2-hydroxyglutarate (2HG) to promote disease progression in acute myeloid leukemia (AML). Thus, an allosteric IDH2 inhibitor, enasidenib (AG-221), which binds to the IDH2 dimer interface to block the production of 2HG by mutant IDH2, was evaluated in a phase I/II trial of patients with IDH2-mutant AML. Enasidenib induced clinical responses, and Intlekofer, Shih, and colleagues investigated mechanisms of resistance in two patients who acquired resistance to enasidenib and continued to disease progression. These patients initially harbored the oncogenic IDH2R140Q mutation, and, at the time of resistance, each patient had acquired a second IDH2 missense mutation (Q316E or I319M). These acquired mutations occurred in trans, on the allele that was not affected by the R140Q mutation. Both the Q316E and I319M mutations occur at the interface where enasidenib binds the IDH2 dimer, blocking the drug interaction. Enasidenib reduced 2HG levels in cells harboring the R140Q mutation, and a secondary Q316E or I319M mutation, in cis or in trans, relieved this suppression of 2HG production, enhancing mutant IDH2 enzymatic activity. However, Q316E or I319M mutations had no effect on 2HG levels when the cooperating R140Q mutation was not present. The second site Q316E or I319M mutations conferred resistance to enasidenib in vitro and in vivo. A patient with acquired resistance to an IDH1 inhibitor who acquired an in cis mutation in IDH1 was also identified. The IDH1 S280F mutation occurred at the at the analogous residue to I319 and was associated with increased 2HG, suggesting that resistance to either IDH2 or IDH1 targeted therapies can occur through second-site mutations in cis or in trans. Taken together, these findings elucidate a mechanism by which second-site IDH2 mutations can promote acquired resistance to enasidenib in patients with AML, and further demonstrate the importance of elevated 2HG production in the IDH2-mutant tumorigenesis.
Intlekofer AM, Shih AH, Wang B, Nazir A, Rustenburg AS, Albanese SK, et al. Acquired resistance to IDH inhibition through trans or cis dimer-interface mutations. Nature 2018;559:125–9.
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