Activation of the MAPK pathway mediates resistance to PI3K inhibitors in chronic lymphocytic leukemia.
Adult
Aged
Cell Line, Tumor
Drug Resistance, Neoplasm
/ drug effects
Enzyme Activation
/ drug effects
Extracellular Signal-Regulated MAP Kinases
/ metabolism
Female
Genome, Human
Humans
Leukemia, Lymphocytic, Chronic, B-Cell
/ drug therapy
MAP Kinase Signaling System
/ drug effects
Male
Middle Aged
Mutation
/ genetics
Phosphoinositide-3 Kinase Inhibitors
/ pharmacology
Proto-Oncogene Proteins c-akt
/ metabolism
Purines
/ pharmacology
Quinazolinones
/ pharmacology
Treatment Outcome
Up-Regulation
/ genetics
Journal
Blood
ISSN: 1528-0020
Titre abrégé: Blood
Pays: United States
ID NLM: 7603509
Informations de publication
Date de publication:
08 07 2021
08 07 2021
Historique:
received:
08
05
2020
accepted:
12
02
2021
pubmed:
9
3
2021
medline:
31
7
2021
entrez:
8
3
2021
Statut:
ppublish
Résumé
Inhibitors of Bruton tyrosine kinase (BTK) and phosphatidylinositol 3-kinase δ (PI3Kδ) that target the B-cell receptor (BCR) signaling pathway have revolutionized the treatment of chronic lymphocytic leukemia (CLL). Mutations associated with resistance to BTK inhibitors have been identified, but limited data are available on mechanisms of resistance to PI3Kδ inhibitors. Here we present findings from longitudinal whole-exome sequencing of cells from patients with multiply relapsed CLL (N = 28) enrolled in trials of PI3K inhibitors. The nonresponder subgroup was characterized by baseline activating mutations in MAP2K1, BRAF, and KRAS genes in 60% of patients. PI3Kδ inhibition failed to inhibit ERK phosphorylation (pERK) in nonresponder CLL cells with and without mutations, whereas treatment with a MEK inhibitor rescued ERK inhibition. Overexpression of MAP2K1 mutants in vitro led to increased basal and inducible pERK and resistance to idelalisib. These data demonstrate that MAPK/ERK activation plays a key role in resistance to PI3Kδ inhibitors in CLL and provide a rationale for therapy with a combination of PI3Kδ and ERK inhibitors.
Identifiants
pubmed: 33684943
pii: S0006-4971(21)00575-9
doi: 10.1182/blood.2020006765
pmc: PMC8493976
doi:
Substances chimiques
Phosphoinositide-3 Kinase Inhibitors
0
Purines
0
Quinazolinones
0
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Extracellular Signal-Regulated MAP Kinases
EC 2.7.11.24
idelalisib
YG57I8T5M0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
44-56Subventions
Organisme : NCI NIH HHS
ID : R01 CA213442
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Informations de copyright
© 2021 by The American Society of Hematology.
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