Foxo1‐rictor Axis Induces Akt Phosphorylation During Cll Cell Adaptation to Bcr Inhibitors: Implications for Combinatorial Therapy
Year: 2023
Type: article
Abstract: Introduction: Although genetic mechanisms of resistance to BCR inhibitors in CLL are well-known, it remains elusive whether non-genetic adaptation mechanisms might exist. We focused on the possible role of Akt pathway as PI3K-Akt activation is the only known factor that rescues the apoptosis induced by BCR deletion in mature B cells in mouse models (Srinivasan et al. Cell, 2009). Methods: We performed transcriptome profiling (Illumina) and analyzed samples obtained from CLL patients before and during ibrutinib or idelalisib therapy (1–12 weeks of therapy, n = 70 patients with 194 samples) and performed gene editing in MEC1 cells to reveal the functional role of FoxO1/Rictor. Results: We observed that during ibrutinib therapy in vivo Akt activity (pAktS473) increases above pre-therapy levels in ∼80% of CLL cases within first 12 weeks of therapy (n = 43; p < 0.005; Figure A). RNA profiling of paired CLL samples obtained before and during ibrutinib (n = 22) or idelalisib therapy (n = 18) revealed that during BCR inhibitor treatment the levels of transcription factor FoxO1 are increased in CLL cells (no BTK or PLCG2 mutations detected during early weeks of therapy). FoxO1 subsequently induces transcription of RICTOR, an essential assembly protein for mTORC2 complex which directly phosphorylates Akt on S473. Knock-out of FoxO1 or Rictor in the MEC1 cell line led to a 70% decrease in pAkt levels (p < 0.0001) and resulted in a growth disadvantage in a competitive growth assay in the presence of ibrutinib (Figure B; p < 0.05). Similar results were obtained with idelalisib, suggesting that the FoxO1-Rictor-pAkt axis does not require BTK or PI3Kδ activity. FoxO1 inhibitor (AS1842856) decreased basal and ibrutinib-induced pAkt levels and blocked anti-IgM-induced pAkt and cMYC (p < 0.01). It also induced primary CLL cells' apoptosis alone (∼40% apoptosis) or more potently in combination with ibrutinib or idelalisib (∼60% apoptosis; Figure C, n = 7). The apoptosis induced by FoxO1 inhibition could not be rescued by CLL cells coculture with HS5 cells or HS5 engineered to produce CD40L+IL21+IL4, and FoxO1 inhibitor blocked proliferation of primary CLL cells induced by these T-cell factors (Figure D). Keywords: chronic lymphocytic leukemia (CLL), tumor biology and heterogeneity Encore Abstract - previously submitted to EHA 2023 This work was supported by the Ministry of Health of the Czech Rep., grant no. NU20-03-00292 and NU22-03-00117. This research was supported by ERC under the European Union’s Horizon 2020 Research and Innovation Programme (grant agreement no. 802644), National Institute for Cancer Research (Programme EXCELES, ID Project No. X22NPO5102) - Funded by the European Union - Next Generation EU, MH CZ-DRO (FNBr, 65269705), and MUNI/A/1224/2022. Conflicts of interests pertinent to the abstract M. S. Davids Consultant or advisory role: AbbVie, Adaptive Biosciences, Aptitude Health, Ascentage Pharma, AstraZeneca, BeiGene, Bio Ascend, BMS, Celgene, Curio Science, Eli Lilly, Genentech, Janssen, Merck, Ono Pharmaceuticals, Research to Practice, Secura Bio, TG Therapeutics, Takeda. Research funding: AbbVie, AstraZeneca, Ascentage Pharma, Genentech, MEI Pharma, Novartis, Surface Oncology, TG Therapeutics. J. R. Brown Consultant or advisory role: Abbvie, Acerta/Astra-Zeneca, BeiGene, Eli Lilly, Genentech/Roche, Grifols Worldwide Operations, Hutchmed, iOnctura, Janssen, MEI Pharma, Numab Therapeutics, Pfizer, Pharmacyclics. Research funding: BeiGene, Gilead, iOnctura, Loxo/Lilly, MEI Pharma, SecuraBio, TG Therapeutics. M. Mraz Travel grants: JANSSEN-CILAG CZ
Source: Hematological Oncology
DOI: 10.1002/hon.3163_23
Authors: L. Ondrisova, V. Seda, E. Hoferkova, G. Chiodin, K. Hlavac, L. Kostalova, G. Mladonicka Pavlasova, D. Filip, P. Faria Zeni, J. Oppelt, A. Panovska, K. Plevova, S. Pospisilova, M. Simkovic, F. Vrbacky, D. Lysak, S. M. Fernandes, M. S. Davids, A. Maiques‐Diaz, S. Charalampopoulou, J. I. Martin‐Subero, J. R. Brown, M. Doubek, F. Forconi, J. Mayer, M. Mraz
Institutions: Masaryk University, University Hospital Brno, Central European Institute of Technology – Masaryk University, University of Southampton, Charles University, University Hospital Hradec Králové, University Hospital Plzen, Dana-Farber Cancer Institute, Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Universitat de Barcelona
Language: English
Subfield: Genetics (clinical)
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4379979903