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

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).

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Publication Details

Journal
Journal of Clinical Investigation
Published
2024-10-22
DOI
https://doi.org/10.1172/jci173770
Citations
12
Primary Topic
FOXO transcription factor regulation
Type
article
Field-Weighted Citation Impact
2.81

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article

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

Lenka Košťálová, Pedro Faria Zeni, Eva Hoferkova, Stacey M. Fernandes et al.
12 citations
Journal of Clinical Investigation
FOXO transcription factor regulation
2.81
article

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

Lenka Košťálová, Pedro Faria Zeni, Eva Hoferkova, Stacey M. Fernandes, Václav Šeda, José I. Martı́n-Subero, Giorgia Chiodin, Daniel Filip, Marek Mráz, Michael Doubek, Gabriela Mladonická Pavlasová, Anna Panovská, Stella Charalampopoulou, Ráchel Víchová, Matthew Steven Davids, Alba Maiqués-Díaz, Josef Večeřa, Filip Vrbacký, Daniel Lysák, Laura Ondrišová, Šárka Pospı́šilová, Karla Plevová, Martin Šimkovič, Francesco Forconi, Karel Souček, Jan Oppelt, Krystof Hlavac, Zuzana Kahounová, Jennifer Brown, Petra Pavelkova, Jiří Mayer
article en
12 citations

Abstract

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).

Journal of Clinical InvestigationVol. 134(23)
Charles University (CZ), Masaryk University (CZ), University Hospital Southampton NHS Foundation Trust (GB), Czech Academy of Sciences, Institute of Biophysics (CZ), Central European Institute of Technology – Masaryk University (CZ), University Hospital Brno (CZ), Dana-Farber Cancer Institute (US), University Hospital Hradec Králové (CZ), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), University of Southampton (GB), Universitat de Barcelona (ES)
Cancer Research UK, European Commission, Ministerstvo Zdravotnictví Ceské Republiky, Masarykova Univerzita
Zero hunger
Openalex Percentile: Top 9%
FOXO transcription factor regulation
2.81
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