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Targeting a lineage-specific PI3Kɣ-Akt signaling module in acute myeloid leukemia using a heterobifunctional degrader

Lois M Kelly1, Justine C Rutter2, Kevin H Lin2

  • 1INSERM UMR 944, IRSL, Saint-Louis Hospital, Paris Cité University, Paris, France.

Nature Cancer
|May 30, 2024
PubMed

Insights

Targeting the PIK3CG/p110γ-PIK3R5/p101 pathway in acute myeloid leukemia (AML) inhibits cancer cell growth. A novel PROTAC molecule effectively degrades PIK3CG, offering a promising new AML treatment strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Targeted cancer therapies face dose-limiting toxicities due to non-specific target engagement.
  • Tissue-restricted or tumor-restricted targets can mitigate toxicity and improve therapeutic efficacy.
  • The PIK3CG/p110γ-PIK3R5/p101 axis is implicated in acute myeloid leukemia (AML) pathogenesis.

Purpose of the Study:

  • To investigate the role of the PIK3CG/p110γ-PIK3R5/p101 axis in AML.
  • To evaluate the efficacy of targeting this axis for AML treatment.
  • To develop novel therapeutic strategies for AML.

Main Methods:

  • Gene silencing of PIK3CG/p110γ or PIK3R5/p101 in AML cells.
  • Assessment of protein kinase B/Akt signaling inhibition.
  • Development and testing of a PIK3CG-targeting proteolysis-targeting chimera (PROTAC).
  • Evaluation of PROTAC efficacy alone and in combination with venetoclax in AML models.

Main Results:

  • Suppression of the PIK3CG/p110γ-PIK3R5/p101 axis inhibits Akt signaling and compromises AML cell fitness.
  • Silencing PIK3CG/p110γ or PIK3R5/p101 sensitizes AML cells to existing therapies.
  • Existing PIK3CG inhibitors lack sustained antileukemic effects.
  • Developed PROTAC molecule effectively degrades PIK3CG and suppresses AML progression.

Conclusions:

  • The PIK3CG/p110γ-PIK3R5/p101 axis is a viable therapeutic target in AML.
  • A novel PIK3CG-degrading PROTAC demonstrates potent antileukemic activity.
  • This PROTAC represents a promising new therapeutic approach for AML, alone or in combination therapy.

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