MOLECULAR MECHANISM OF NON-GENETIC ADAPTATION TO BTK INHIBITOR THERAPY IN CLL

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A14740%2F24%3A00137880" target="_blank" >RIV/00216224:14740/24:00137880 - isvavai.cz</a>

Result on the web

<a href="https://www.hematology2024.cz/sbornik-abstrakt-zaznam-sjezdu/" target="_blank" >https://www.hematology2024.cz/sbornik-abstrakt-zaznam-sjezdu/</a>

DOI - Digital Object Identifier

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Result language

angličtina

Original language name

MOLECULAR MECHANISM OF NON-GENETIC ADAPTATION TO BTK INHIBITOR THERAPY IN CLL

Original language description

Genetic mechanisms of resistance to BTK inhibitors in CLL have been described. However, it remains unknown whether non-genetic adaptation to BTK inhibitors might exist. We focused on the possible role of the Akt pathway since, in mouse models, PI3K-Akt activation rescues the apoptosis induced by BCR deletion in mature B cells (Srinivasan et al. Cell, 2009). We show that in ~70% of CLL cases, ibrutinib increases Akt activity (pAktS473) above pretherapy levels (31 patients with 87 samples; P &lt; 0.005). pAkt was also restored in ibrutinib treated MEC1 cells (P &lt; 0.05). Importantly, CLL cells obtained during ibrutinib therapy invivo were highly sensitive (90% apoptosis) to Akt inhibitor MK2206. RNA profiling of paired CLL samples obtained before and during ibrutinib (N = 22) or singleagent idelalisib therapy (N = 18) identified 16 differentially expressed mRNAs (with both drugs) involved in the PI3K-Akt pathway. Rictor induction was particularly notable since it is an essential assembly protein for mTORC2, which is known to phosphorylate Akt directly on S473 (Sarbassov et al. 2005). Analysis of samples obtained during therapy and genome-editing experiments in MEC1 cells revealed that transcription factor FoxO1 is directly responsible for Rictor/pAkt activation during ibrutinib treatment, and FOXO1 is required for adaptation to BTK inhibitors. FoxO1 inhibitor (AS1842856) decreased pAkt levels, induced apoptosis alone (~40% CLL cell killing) or more potently in combination with ibrutinib (~60% apoptosis; N = 7). In summary we describe the first non-genetic adaptation to targeted therapy with BCR inhibitors in CLL.

Czech name

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Czech description

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Type

O - Miscellaneous

CEP classification

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OECD FORD branch

30204 - Oncology

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2024

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů