Resistance to mutant IDH inhibitors in acute myeloid leukemia: Molecular mechanisms and therapeutic strategies

Mutant isocitrate dehydrogenase 1/2 (mIDH1/2) is a promising target for the treatment of cancer. The FDA approved two molecular entities, ivosidenib and enasidenib, which target mIDH1 and mIDH2, respectively, for the treatment of relapsed/refractory acute myeloid leukemia (R/R AML). However, the alarming emergence of drug resistance to ivosidenib and enasidenib, a low response rate and relapse after short-term remission raised concerns about therapeutic options. Several mechanistic investigations of the resistance to these two drugs were performed, and multiple rational therapeutic strategies were proposed. The present review describes the primary and secondary resistance mechanisms of ivosidenib or enasidenib and the corresponding strategies for preventing drug resistance in detail. We discuss the opportunities and challenges for exploiting the next generation of mIDH1/2 inhibitors and translating the combination therapies presented in this paper into clinical applications for the treatment of the nonresponding or relapsed AML patients with IDH mutations.