2024
Ondrisova, Laura; Seda, Vaclav; Hlavac, Krystof; Pavelkova, Petra; Hoferkova, Eva; Chiodin, Giorgia; Kostalova, Lenka; Pavlasova, Gabriela Mladonicka; Filip, Daniel; Vecera, Josef; Zeni, Pedro Faria; Oppelt, Jan; Kahounova, Zuzana; Vichova, Rachel; Soucek, Karel; Panovska, Anna; Plevova, Karla; Pospisilova, Sarka; Simkovic, Martin; Vrbacky, Filip; Lysak, Daniel; Fernandes, Stacey M.; Davids, Matthew S.; Maiques-Diaz, Alba; Charalampopoulou, Stella; Martin-Subero, Jose I.; Brown, Jennifer R.; Doubek, Michael; Forconi, Francesco; Mayer, Jiri; Mraz, Marek
FoxO1/Rictor axis induces a non-genetic adaptation to Ibrutinib via Akt activation in chronic lymphocytic leukemia. Journal Article
In: The Journal of clinical investigation, pp. e173770, 2024, ISSN: 1558-8238 0021-9738, (Place: United States).
Abstract | Links | BibTeX | Tags: Drug therapy, Hematology, Leukemias, Oncology, Signal Transduction
@article{ondrisova_foxo1rictor_2024,
title = {FoxO1/Rictor axis induces a non-genetic adaptation to Ibrutinib via Akt activation in chronic lymphocytic leukemia.},
author = {Laura Ondrisova and Vaclav Seda and Krystof Hlavac and Petra Pavelkova and Eva Hoferkova and Giorgia Chiodin and Lenka Kostalova and Gabriela Mladonicka Pavlasova and Daniel Filip and Josef Vecera and Pedro Faria Zeni and Jan Oppelt and Zuzana Kahounova and Rachel Vichova and Karel Soucek and Anna Panovska and Karla Plevova and Sarka Pospisilova and Martin Simkovic and Filip Vrbacky and Daniel Lysak and Stacey M. Fernandes and Matthew S. Davids and Alba Maiques-Diaz and Stella Charalampopoulou and Jose I. Martin-Subero and Jennifer R. Brown and Michael Doubek and Francesco Forconi and Jiri Mayer and Marek Mraz},
doi = {10.1172/JCI173770},
issn = {1558-8238 0021-9738},
year = {2024},
date = {2024-10-01},
journal = {The Journal of clinical investigation},
pages = {e173770},
abstract = {BTK inhibitor therapy induces peripheral blood lymphocytosis in chronic lymphocytic leukemia (CLL) lasting for several months. It remains unclear whether non-genetic 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 pre-therapy 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 FoxO1 transcription factor, which induces expression of Rictor, an assembly protein for mTORC2 protein complex that directly phosphorylates Akt at serine 473 (S473). Knock-out 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. FoxO1/Rictor/pAktS473 axis represents an early non-genetic adaptation to 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).},
note = {Place: United States},
keywords = {Drug therapy, Hematology, Leukemias, Oncology, Signal Transduction},
pubstate = {published},
tppubtype = {article}
}
BTK inhibitor therapy induces peripheral blood lymphocytosis in chronic lymphocytic leukemia (CLL) lasting for several months. It remains unclear whether non-genetic 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 pre-therapy 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 FoxO1 transcription factor, which induces expression of Rictor, an assembly protein for mTORC2 protein complex that directly phosphorylates Akt at serine 473 (S473). Knock-out 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. FoxO1/Rictor/pAktS473 axis represents an early non-genetic adaptation to 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).