Overcoming Acquired Epigenetic Resistance to BTK Inhibitors.
Journal
Blood cancer discovery
ISSN: 2643-3249
Titre abrégé: Blood Cancer Discov
Pays: United States
ID NLM: 101764786
Informations de publication
Date de publication:
Nov 2021
Nov 2021
Historique:
received:
12
04
2021
revised:
17
06
2021
accepted:
31
08
2021
entrez:
15
11
2021
pubmed:
16
11
2021
medline:
16
11
2021
Statut:
epublish
Résumé
The use of Bruton tyrosine kinase (BTK) inhibitors to block B-cell receptor (BCR)-dependent NF-κB activation in lymphoid malignancies has been a major clinical advance, yet acquired therapeutic resistance is a recurring problem. We modeled the development of resistance to the BTK inhibitor ibrutinib in the activated B-cell (ABC) subtype of diffuse large B-cell lymphoma, which relies on chronic active BCR signaling for survival. The primary mode of resistance was epigenetic, driven in part by the transcription factor TCF4. The resultant phenotypic shift altered BCR signaling such that the GTPase RAC2 substituted for BTK in the activation of phospholipase Cγ2, thereby sustaining NF-κB activity. The interaction of RAC2 with phospholipase Cγ2 was also increased in chronic lymphocytic leukemia cells from patients with persistent or progressive disease on BTK inhibitor treatment. We identified clinically available drugs that can treat epigenetic ibrutinib resistance, suggesting combination therapeutic strategies. In diffuse large B-cell lymphoma, we show that primary resistance to BTK inhibitors is due to epigenetic rather than genetic changes that circumvent the BTK blockade. We also observed this resistance mechanism in chronic lymphocytic leukemia, suggesting that epigenetic alterations may contribute more to BTK inhibitor resistance than currently thought.
Identifiants
pubmed: 34778802
doi: 10.1158/2643-3230.BCD-21-0063
pii: 2643-3230.BCD-21-0063
pmc: PMC8580621
doi:
Substances chimiques
Protein Kinase Inhibitors
0
Agammaglobulinaemia Tyrosine Kinase
EC 2.7.10.2
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Langues
eng
Pagination
630-647Subventions
Organisme : NCI NIH HHS
ID : T32 CA203703
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
©2021 American Association for Cancer Research.
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