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

  • Nat Cancer. 2024 May 30. doi: 10.1038/s43018-024-00782-5.
Lois M Kelly  #  1 ,  Justine C Rutter  #  2 ,  Kevin H Lin  #  2 ,  Frank Ling  1 ,  Matthieu Duchmann  1 ,  Emmanuelle Latour  1 ,  Nadia Arang  3  4 ,  Hélène Pasquer  1 ,  Duong Ho Nhat  1 ,  Juliette Charles  1 ,  Shane T Killarney  2 ,  Hazel X Ang  2 ,  Federica Namor  1 ,  Cécile Culeux  1 ,  Bérangère Lombard  5 ,  Damarys Loew  5 ,  Danielle L Swaney  3  4  6 ,  Nevan J Krogan  3  4  6 ,  Luc Brunel  7 ,  Élodie Carretero  7 ,  Pascal Verdié  7 ,  Muriel Amblard  7 ,  Sofiane Fodil  8 ,  Tony Huynh  8 ,  Marie Sebert  1  8 ,  Lionel Adès  1  8 ,  Emmanuel Raffoux  1  8 ,  Nina Fenouille  1 ,  Raphaël Itzykson  1  8 ,  Camille Lobry  1 ,  Lina Benajiba  1  9 ,  Antoine Forget  3  4 ,  Anthony R Martin  10 ,  Kris C Wood  11 ,  Alexandre Puissant  12
Affiliations
  • 1. INSERM UMR 944, IRSL, Saint-Louis Hospital, Paris Cité University, Paris, France.
  • 2. Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA.
  • 3. Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA, USA.
  • 4. Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA.
  • 5. Curie Institute, Mass Spectrometry and Proteomics Facility, PSL Research University, Paris, France.
  • 6. Gladstone Institutes, San Francisco, California, USA.
  • 7. IBMM, University of Montpellier, CNRS, ENSCM, Montpellier, France.
  • 8. Department of Hematology and Immunology, Saint-Louis Hospital, AP-HP, Paris Cité University, Paris, France.
  • 9. Clinical Investigation Center, Saint-Louis Hospital, AP-HP, Paris Cité University, Paris, France.
  • 10. IBMM, University of Montpellier, CNRS, ENSCM, Montpellier, France. [email protected].
  • 11. Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA. [email protected].
  • 12. INSERM UMR 944, IRSL, Saint-Louis Hospital, Paris Cité University, Paris, France. [email protected].
  • # Contributed equally.
PMID: 38816660 DOI: 10.1038/s43018-024-00782-5
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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