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Functional characterization of the PI3K/AKT/MTOR signaling pathway for targeted therapy in B-precursor acute

Patricia K Grüninger1, Franziska Uhl1, Heike Herzog1

  • 1Department of Hematology/Oncology/Stem Cell Transplantation, University of Freiburg Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Cancer Gene Therapy
|July 6, 2022
PubMed

Insights

B-cell acute lymphoblastic leukemia (B-ALL) cells rely on the MTOR signaling pathway for survival. Inhibiting MTOR and AKT synergistically reduces cancer cell proliferation, suggesting a promising combination therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • B-cell acute lymphoblastic leukemia (B-ALL) is driven by activated signaling pathways crucial for leukemia cell survival and proliferation.
  • Identifying key dependencies in B-ALL is essential for developing targeted therapies.

Purpose of the Study:

  • To investigate the dependency of B-ALL cells on the MTOR signaling pathway and its upstream components (PI3K/AKT, MTORC1, MTORC2).
  • To explore the potential of combined MTOR and AKT inhibition as a therapeutic strategy for B-ALL.

Main Methods:

  • Unbiased shRNA library screen to identify key genes in B-ALL signaling.
  • Genetic and pharmacologic inhibition of MTOR, AKT, MTORC1, and MTORC2.
  • In vitro and in vivo proliferation and survival assays.
  • Cell metabolomics to analyze metabolic changes.

Main Results:

  • MTOR was identified as a critical dependency in human B-ALL E2A-PBX1+ RCH-ACV cells.
  • Combined inhibition of MTOR and AKT demonstrated synergistic effects on reducing B-ALL cell proliferation across various karyotypes.
  • B-ALL cells showed a greater dependence on the MTORC2 complex than MTORC1.
  • MTOR inhibition led to increased reliance on fatty acid metabolism for energy production in B-ALL cells.

Conclusions:

  • B-ALL cells are critically dependent on the PI3K/AKT/MTOR signaling pathway.
  • Targeting this pathway, particularly with combined small molecule inhibitors, shows significant therapeutic potential for B-ALL treatment.
  • Altering cellular metabolism, specifically increasing fatty acid utilization, presents a novel therapeutic vulnerability in B-ALL.

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