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Stepwise evolution of therapy resistance in AML

Philippe Gui1, Trever G Bivona1

  • 1Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.

Cancer Cell
|June 25, 2021
PubMed

Insights

Relapse in acute myeloid leukemia (AML) patients treated with FLT3 inhibitors (FLT3i) involves residual cancer cells surviving and expanding. This study reveals how microenvironment factors drive early resistance, which progresses to mutation-driven late resistance to gilteritinib.

Area of Science:

  • Hematology
  • Oncology
  • Cancer Biology

Background:

  • Relapse in acute myeloid leukemia (AML) is a significant challenge, often driven by treatment resistance.
  • FLT3 inhibitors (FLT3i) are crucial in AML therapy, but resistance remains a major hurdle.
  • Understanding the mechanisms of resistance is vital for improving patient outcomes.

Purpose of the Study:

  • To investigate the stepwise evolution of resistance to gilteritinib, a FLT3 inhibitor, in AML.
  • To differentiate between early microenvironment-driven resistance and late mutation-driven resistance.
  • To elucidate the mechanisms underlying treatment failure in FLT3-mutated AML.

Main Methods:

  • Utilized a multifaceted approach combining in vitro and in vivo models.
  • Employed techniques to analyze cellular responses and genetic alterations.
  • Characterized the role of the tumor microenvironment in resistance development.

Main Results:

  • Demonstrated that early resistance to gilteritinib is influenced by the tumor microenvironment.
  • Showed a transition from microenvironment-dependent resistance to acquired mutations driving late-stage resistance.
  • Identified specific pathways and cellular interactions contributing to gilteritinib resistance.

Conclusions:

  • Resistance to FLT3 inhibitors in AML is a dynamic, stepwise process.
  • The tumor microenvironment plays a critical role in the initial stages of resistance.
  • Acquired mutations are key drivers of late-stage, persistent resistance to gilteritinib, necessitating further therapeutic strategies.

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