Leukemia stemness and co-occurring mutations drive resistance to IDH inhibitors in acute myeloid leukemia

Feng Wang,Erika J Thompson,Hagop M Kantarjian,Guillermo Garcia‐Manero ,Courtney D Dinardo,Kyle J Macbeth,Kiyomi Morita,Xinwei Li ,Marina Konopleva,Kapil N Bhalla,Elias Jabbour,Jianhua Zhang,Jairo Matthews ,Keyur P Patel,Curtis Gumbs,Yuanqing Yan,Mark G Frattini ,Xingzhi Song,Tomoyuki Tanaka,P Andrew Futreal,Ken Furudate,Bin Wu,Tapan M Kadia,Latasha Little ,Farhad Ravandi,Koichi Takahashi

doi:10.1038/s41467-021-22874-x

Abstract

Allosteric inhibitors of mutant IDH1 or IDH2 induce terminal differentiation of the mutant leukemic blasts and provide durable clinical responses in approximately 40% of acute myeloid leukemia (AML) patients with the mutations. However, primary resistance and acquired resistance to the drugs are major clinical issues. To understand the molecular underpinnings of clinical resistance to IDH inhibitors (IDHi), we perform multipronged genomic analyses (DNA sequencing, RNA sequencing and cytosine methylation profiling) in longitudinally collected specimens from 60 IDH1- or IDH2-mutant AML patients treated with the inhibitors. The analysis reveals that leukemia stemness is a major driver of primary resistance to IDHi, whereas selection of mutations in RUNX1/CEBPA or RAS-RTK pathway genes is the main driver of acquired resistance to IDHi, along with BCOR, homologous IDH gene, and TET2. These data suggest that targeting stemness and certain high-risk co-occurring mutations may overcome resistance to IDHi in AML.

Highlights

Allosteric inhibitors of mutant IDH1 or IDH2 induce terminal differentiation of the mutant leukemic blasts and provide durable clinical responses in approximately 40% of acute myeloid leukemia (AML) patients with the mutations
Using a multipronged genomic analysis on longitudinally collected samples from the clinical trials, we studied genetic and epigenetic correlates of response to IDH inhibitors (IDHi) in AML
While confirming previous findings about the role of certain co-occurring mutations (RAS and RUNX1) in primary resistance to IDHi9, we revealed that leukemia stemness is associated with IDHi primary resistance

Summary

Introduction

Allosteric inhibitors of mutant IDH1 or IDH2 induce terminal differentiation of the mutant leukemic blasts and provide durable clinical responses in approximately 40% of acute myeloid leukemia (AML) patients with the mutations. In the majority of the responders, IDH mutations are stably detected in matured neutrophils, indicating that the clinical response to the inhibitors is mediated by the terminal differentiation of leukemic blasts[9]. This mechanism of action is consistent with the observations in preclinical models[12,13] and patient-derived xenograft models[14], as well as in longitudinally profiled hematopoietic stem cell populations from patients who responded to enasidenib[15]. The same group of investigators reported four cases of IDH isoform switching, which refers to the emergence of the mutation in homologous IDH gene counterpart during the inhibition of the other IDH mutant

Methods

Results

Conclusion