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Actin cytoskeleton deregulation confers midostaurin resistance in FLT3-mutant acute myeloid leukemia

Andoni Garitano-Trojaola1, Ana Sancho2,3, Ralph Götz4

  • 1Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany.

Communications Biology
|June 26, 2021
PubMed

Insights

Resistance to midostaurin in acute myeloid leukemia (AML) with FLT3-ITD mutations is linked to RAC1-driven changes in cell structure. Combining midostaurin with venetoclax and a RAC1 inhibitor may overcome this resistance.

Area of Science:

  • Hematology
  • Molecular Biology
  • Cancer Research

Background:

  • FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) is a common mutation in acute myeloid leukemia (AML), associated with poor prognosis.
  • Current FLT3 inhibitors like midostaurin do not fully eliminate FLT3-ITD+ AML, necessitating novel therapeutic strategies.

Purpose of the Study:

  • To investigate the role of RAC1-dependent actin cytoskeleton remodeling in midostaurin resistance in FLT3-ITD+ AML.
  • To identify potential therapeutic targets and combinations to overcome midostaurin resistance.

Main Methods:

  • Analysis of RAC1 hyperactivation and its downstream effects on N-WASP and BCL-2.
  • Assessment of actin polymerization, cell stiffness, and adhesion to mesenchymal stromal cells (MSCs).
  • Evaluation of combination therapies including midostaurin, venetoclax, and a RAC1 inhibitor (Eht1864) in AML cell lines and primary samples.

Main Results:

  • RAC1 hyperactivation promotes midostaurin resistance by increasing N-WASP phosphorylation and BCL-2 levels.
  • Increased actin polymerization, cell stiffness, and MSC adhesion, mediated by RAC1/N-WASP/ARP2/3 complex, serve as biomarkers for resistance.
  • Combination therapy with midostaurin, venetoclax, and Eht1864 effectively overcomes resistance in preclinical models.

Conclusions:

  • RAC1-dependent actin remodeling is a key mechanism of midostaurin resistance in FLT3-ITD+ AML.
  • Targeting RAC1, BCL-2, and FLT3 concurrently offers a promising new therapeutic approach for eradicating resistant AML.

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