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Clinical resistance to crenolanib in acute myeloid leukemia due to diverse molecular mechanisms

Haijiao Zhang1,2, Samantha Savage1,2, Anna Reister Schultz1,2

  • 1Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University Knight Cancer Institute, Portland, 97239, OR, USA.

Nature Communications
|January 18, 2019
PubMed

Insights

Crenolanib resistance in acute myeloid leukemia (AML) involves new mutations in NRAS, IDH2, TET2, and IDH1, not FLT3. Combination therapies may overcome resistance.

Area of Science:

  • Hematology
  • Oncology
  • Genetics

Background:

  • FMS-like tyrosine kinase 3 (FLT3) mutations are common in acute myeloid leukemia (AML) and associated with poor outcomes.
  • Crenolanib, a FLT3 inhibitor, shows efficacy but responses are often temporary, leading to relapse.

Purpose of the Study:

  • To investigate the genetic mechanisms underlying crenolanib resistance in AML patients.
  • To identify novel mutations that emerge or are selected under crenolanib treatment.

Main Methods:

  • Whole exome sequencing was performed on AML patient samples before and after crenolanib treatment.
  • Analysis focused on identifying acquired mutations and their association with treatment response.

Main Results:

  • Crenolanib treatment did not frequently induce secondary FLT3 mutations or gatekeeper mutations.
  • Acquired mutations in NRAS and IDH2 were observed, often in FLT3-independent subclones.
  • Mutations in TET2 and IDH1 were enriched in patients with poor responses to crenolanib.
  • Other patients showed expanded mutations in epigenetic regulators, transcription factors, and cohesion factors.

Conclusions:

  • Resistance to crenolanib in AML is driven by diverse genetic and epigenetic alterations, rather than solely FLT3 mutations.
  • Emergence of NRAS, IDH2, TET2, and IDH1 mutations contributes to treatment failure.
  • Experimental models suggest that drug combinations can restore sensitivity to crenolanib.

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