Targeting phosphatidylinositol 3 kinase-β and -δ for Bruton tyrosine kinase resistance in diffuse large B-cell lymphoma.
Journal
Blood advances
ISSN: 2473-9537
Titre abrégé: Blood Adv
Pays: United States
ID NLM: 101698425
Informations de publication
Date de publication:
22 09 2020
22 09 2020
Historique:
received:
18
02
2020
accepted:
29
07
2020
entrez:
14
9
2020
pubmed:
15
9
2020
medline:
15
5
2021
Statut:
ppublish
Résumé
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma; 40% of patients relapse after a complete response or are refractory to therapy. To survive, the activated B-cell (ABC) subtype of DLBCL relies upon B-cell receptor signaling, which can be modulated by the activity of Bruton tyrosine kinase (BTK). Targeting BTK with ibrutinib, an inhibitor, provides a therapeutic approach for this subtype of DLBCL. However, non-Hodgkin lymphoma is often resistant to ibrutinib or acquires resistance soon after exposure. We explored how this resistance develops. We generated 3 isogenic ibrutinib-resistant DLBCL cell lines and investigated the deregulated pathways known to be associated with tumorigenic properties. Reduced levels of BTK and enhanced phosphatidylinositol 3-kinase (PI3K)/AKT signaling were hallmarks of these ibrutinib-resistant cells. Upregulation of PI3K-β expression was demonstrated to drive resistance in ibrutinib-resistant cells, and resistance was reversed by the blocking activity of PI3K-β/δ. Treatment with the selective PI3K-β/δ dual inhibitor KA2237 reduced both tumorigenic properties and survival-based PI3K/AKT/mTOR signaling of these ibrutinib-resistant cells. In addition, combining KA2237 with currently available chemotherapeutic agents synergistically inhibited metabolic growth. This study elucidates the compensatory upregulated PI3K/AKT axis that emerges in ibrutinib-resistant cells.
Identifiants
pubmed: 32926124
pii: S2473-9529(20)31520-2
doi: 10.1182/bloodadvances.2020001685
pmc: PMC7509871
doi:
Substances chimiques
Phosphatidylinositol 3-Kinase
EC 2.7.1.137
Agammaglobulinaemia Tyrosine Kinase
EC 2.7.10.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4382-4392Informations de copyright
© 2020 by The American Society of Hematology.
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