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The AML microenvironment catalyzes a stepwise evolution to gilteritinib resistance

Sunil K Joshi1, Tamilla Nechiporuk2, Daniel Bottomly3

  • 1Knight Cancer Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA; Department of Physiology & Pharmacology, School of Medicine, Oregon Health & Science University, Portland, OR, USA; Division of Hematology & Medical Oncology, Department of Medicine, Oregon Health & Science University, Portland, OR, USA.

Cancer Cell
|June 25, 2021
PubMed

Insights

Gilteritinib resistance in FLT3-mutated acute myeloid leukemia (AML) evolves in stages. Early resistance involves the bone marrow microenvironment, while late resistance stems from intrinsic cell changes and NRAS mutations. Targeting Aurora kinase B (AURKB) with gilteritinib may overcome resistance.

Area of Science:

  • Hematology
  • Oncology
  • Molecular Biology

Background:

  • Acute myeloid leukemia (AML) with FLT3 mutations poses treatment challenges.
  • Gilteritinib is a targeted therapy for FLT3-mutated AML.
  • Mechanisms of gilteritinib resistance are not fully understood.

Purpose of the Study:

  • To elucidate the stepwise evolution of gilteritinib resistance in FLT3-mutated AML.
  • To identify key molecular and cellular mechanisms driving early and late resistance.
  • To explore therapeutic strategies to overcome gilteritinib resistance.

Main Methods:

  • Integration of whole-exome sequencing, CRISPR-Cas9 gene editing, metabolomics, and proteomics.
  • Pharmacologic approaches to assess drug sensitivity and resistance.
  • Modeling of resistance evolution using cell cultures and primary patient samples.

Main Results:

  • Early gilteritinib resistance is mediated by the bone marrow microenvironment, leading to metabolic reprogramming and Aurora kinase B (AURKB) dependency.
  • Late resistance is characterized by the expansion of pre-existing NRAS mutant subclones and ongoing metabolic adaptation.
  • Pharmacological inhibition of AURKB resensitizes resistant AML cells to gilteritinib.

Conclusions:

  • Gilteritinib resistance in FLT3-mutated AML develops through distinct early and late phases.
  • Targeting AURKB in combination with gilteritinib shows promise for overcoming early resistance.
  • This combinatorial strategy may prevent the emergence of more aggressive, resistant AML clones.
Keywords:
AMLAurora kinase BFLT3NRASdrug resistancegilteritiniblipid metabolismquizartinibtumor microenvironmenttyrosine kinase inhibitor

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