FoxO1/Rictor axis induces a non-genetic adaptation to Ibrutinib via Akt activation in chronic lymphocytic leukemia

• Authors: ONDRIŠOVÁ Laura; ŠEDA Václav; HLAVÁČ Kryštof; PAVELKOVÁ Petra; HOFERKOVÁ Eva; CHIODIN Giorgia; KOŠŤÁLOVÁ Lenka; MLADONICKÁ PAVLASOVÁ Gabriela; FILIP Daniel; VEČEŘA Josef; FARIA ZENI Pedro; OPPELT Jan; KAHOUNOVÁ Zuzana; VICHOVA Rachel; SOUČEK Karel; PANOVSKÁ Anna; PLEVOVÁ Karla; POSPÍŠILOVÁ Šárka; ŠIMKOVIČ Martin; VRBACKÝ Filip; LYSÁK Daniel; FERNANDES Stacey M.; DAVIDS M.S.; MAIQUES-DIAZ Alba; CHARALAMPOPOULOU Stella; MARTIN-SUBERO Jose I.; BROWN Jenifer R.; DOUBEK Michael; MAYER Jiří; MRÁZ Marek
• Year of publication: 2024
• Type: Article in Periodical
• Magazine / Source: The Journal of Clinical Investigation
• MU Faculty or unit: Central European Institute of Technology
• web: https://www.jci.org/articles/view/173770?utm_campaign=cover-page&utm_content=short_url&utm_medium=pdf&utm_source=content
• Doi: http://dx.doi.org/10.1172/JCI173770

Attached files

• 173770.1-20241017142851-covered-e0fd13ba177f913fd3156f593ead4cfd.pdf

• Description: 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 PI3K? 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)