FoxO1/Rictor axis induces a nongenetic adaptation to ibrutinib via Akt activation in chronic lymphocytic leukemia.

Autor: Ondrisova L; Molecular Medicine, CEITEC Masaryk University, Brno, Czechia.; Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czechia., Seda V; Molecular Medicine, CEITEC Masaryk University, Brno, Czechia.; Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czechia., Hlavac K; Molecular Medicine, CEITEC Masaryk University, Brno, Czechia.; Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czechia., Pavelkova P; Molecular Medicine, CEITEC Masaryk University, Brno, Czechia.; Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czechia., Hoferkova E; Molecular Medicine, CEITEC Masaryk University, Brno, Czechia.; Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czechia., Chiodin G; Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom., Kostalova L; Molecular Medicine, CEITEC Masaryk University, Brno, Czechia.; Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czechia., Mladonicka Pavlasova G; Molecular Medicine, CEITEC Masaryk University, Brno, Czechia., Filip D; Molecular Medicine, CEITEC Masaryk University, Brno, Czechia.; Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czechia., Vecera J; Molecular Medicine, CEITEC Masaryk University, Brno, Czechia.; Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czechia., Zeni PF; Molecular Medicine, CEITEC Masaryk University, Brno, Czechia., Oppelt J; Molecular Medicine, CEITEC Masaryk University, Brno, Czechia., Kahounova Z; Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czechia., Vichova R; Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czechia., Soucek K; Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czechia., Panovska A; Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czechia., Plevova K; Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czechia., Pospisilova S; Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czechia., Simkovic M; Fourth Department of Internal Medicine-Haematology, University Hospital Hradec Kralove and Faculty of Medicine Hradec Kralove, Charles University, Prague, Czechia., Vrbacky F; Fourth Department of Internal Medicine-Haematology, University Hospital Hradec Kralove and Faculty of Medicine Hradec Kralove, Charles University, Prague, Czechia., Lysak D; Department of Haematology and Oncology, University Hospital Pilsen, Pilsen, Czechia., Fernandes SM; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA., Davids MS; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA., Maiques-Diaz A; Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain., Charalampopoulou S; Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain., Martin-Subero JI; Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain., Brown JR; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA., Doubek M; Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czechia., Forconi F; Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.; Haematology Department, Cancer Care Directorate, University Hospital Southampton NHS Trust, Southampton, United Kingdom., Mayer J; Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czechia., Mraz M; Molecular Medicine, CEITEC Masaryk University, Brno, Czechia.; Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czechia.
Jazyk: angličtina
Zdroj: The Journal of clinical investigation [J Clin Invest] 2024 Oct 22; Vol. 134 (23). Date of Electronic Publication: 2024 Oct 22.
DOI: 10.1172/JCI173770
Abstrakt: Bruton tyrosine kinase (BTK) inhibitor therapy induces peripheral blood lymphocytosis in chronic lymphocytic leukemia (CLL), which lasts for several months. It remains unclear whether nongenetic adaptation mechanisms exist, allowing CLL cells' survival during BTK inhibitor-induced lymphocytosis and/or playing a role in therapy resistance. We show that in approximately 70% of CLL cases, ibrutinib treatment in vivo increases Akt activity above pretherapy levels within several weeks, leading to compensatory CLL cell survival and a more prominent lymphocytosis on therapy. Ibrutinib-induced Akt phosphorylation (pAktS473) is caused by the upregulation of Forkhead box protein O1 (FoxO1) transcription factor, which induces expression of Rictor, an assembly protein for the mTORC2 protein complex that directly phosphorylates Akt at serine 473 (S473). Knockout or inhibition of FoxO1 or Rictor led to a dramatic decrease in Akt phosphorylation and growth disadvantage for malignant B cells in the presence of ibrutinib (or PI3K inhibitor idelalisib) in vitro and in vivo. The FoxO1/Rictor/pAktS473 axis represents an early nongenetic adaptation to B cell receptor (BCR) inhibitor therapy not requiring PI3Kδ or BTK kinase activity. We further demonstrate that FoxO1 can be targeted therapeutically and its inhibition induces CLL cells' apoptosis alone or in combination with BTK inhibitors (ibrutinib, acalabrutinib, pirtobrutinib) and blocks their proliferation triggered by T cell factors (CD40L, IL-4, and IL-21).
Databáze: MEDLINE