Targeting a lineage-specific PI3Kɣ–Akt signaling module in acute myeloid leukemia using a heterobifunctional degrader molecule - Inserm - Institut national de la santé et de la recherche médicale Access content directly
Journal Articles Nature Cancer Year : 2024

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

Justine Rutter
Shane Killarney
Hazel Ang
Bérangère Lombard
Damarys Loew
Kris Wood
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Abstract

Dose-limiting toxicity poses a major limitation to the clinical utility of targeted cancer therapies, often arising from target engagement in nonmalignant tissues. This obstacle can be minimized by targeting cancer dependencies driven by proteins with tissue-restricted and/or tumor-restricted expression. In line with another recent report, we show here that, in acute myeloid leukemia (AML), suppression of the myeloid-restricted PIK3CG/p110γ–PIK3R5/p101 axis inhibits protein kinase B/Akt signaling and compromises AML cell fitness. Furthermore, silencing the genes encoding PIK3CG/p110γ or PIK3R5/p101 sensitizes AML cells to established AML therapies. Importantly, we find that existing small-molecule inhibitors against PIK3CG are insufficient to achieve a sustained long-term antileukemic effect. To address this concern, we developed a proteolysis-targeting chimera (PROTAC) heterobifunctional molecule that specifically degrades PIK3CG and potently suppresses AML progression alone and in combination with venetoclax in human AML cell lines, primary samples from patients with AML and syngeneic mouse models.
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Year Month Jours
Avant la publication
Saturday, November 30, 2024
Embargoed file
Saturday, November 30, 2024
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Dates and versions

hal-04598240 , version 1 (06-06-2024)

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Lois Kelly, Justine Rutter, Kevin Lin, Frank Ling, Matthieu Duchmann, et al.. Targeting a lineage-specific PI3Kɣ–Akt signaling module in acute myeloid leukemia using a heterobifunctional degrader molecule. Nature Cancer, inPress, Online ahead of print. ⟨10.1038/s43018-024-00782-5⟩. ⟨hal-04598240⟩
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