Functional Testing to Characterize and Stratify PI3K Inhibitor Responses in Chronic Lymphocytic Leukemia.
Antineoplastic Agents
/ pharmacology
Bridged Bicyclo Compounds, Heterocyclic
Caspase 3
Humans
Leukemia, Lymphocytic, Chronic, B-Cell
/ drug therapy
Leukocytes, Mononuclear
/ metabolism
Phosphatidylinositol 3-Kinases
/ metabolism
Phosphoinositide-3 Kinase Inhibitors
Proto-Oncogene Proteins c-bcl-2
/ genetics
Quinazolinones
/ pharmacology
Sulfonamides
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
14 10 2022
14 10 2022
Historique:
received:
15
04
2022
revised:
17
06
2022
accepted:
19
08
2022
pubmed:
24
8
2022
medline:
18
10
2022
entrez:
23
8
2022
Statut:
ppublish
Résumé
PI3K inhibitors (PI3Ki) are approved for relapsed chronic lymphocytic leukemia (CLL). Although patients may show an initial response to these therapies, development of treatment intolerance or resistance remain clinical challenges. To overcome these, prediction of individual treatment responses based on actionable biomarkers is needed. Here, we characterized the activity and cellular effects of 10 PI3Ki and investigated whether functional analyses can identify treatment vulnerabilities in PI3Ki-refractory/intolerant CLL and stratify responders to PI3Ki. Peripheral blood mononuclear cell samples (n = 51 in total) from treatment-naïve and PI3Ki-treated patients with CLL were studied. Cells were profiled against 10 PI3Ki and the Bcl-2 antagonist venetoclax. Cell signaling and immune phenotypes were analyzed by flow cytometry. Cell viability was monitored by detection of cleaved caspase-3 and the CellTiter-Glo assay. pan-PI3Kis were most effective at inhibiting PI3K signaling and cell viability, and showed activity in CLL cells from both treatment-naïve and idelalisib-refractory/intolerant patients. CLL cells from idelalisib-refractory/intolerant patients showed overall reduced protein phosphorylation levels. The pan-PI3Ki copanlisib, but not the p110δ inhibitor idelalisib, inhibited PI3K signaling in CD4+ and CD8+ T cells in addition to CD19+ B cells, but did not significantly affect T-cell numbers. Combination treatment with a PI3Ki and venetoclax resulted in synergistic induction of apoptosis. Analysis of drug sensitivities to 73 drug combinations and profiling of 31 proteins stratified responders to idelalisib and umbralisib, respectively. Our findings suggest novel treatment vulnerabilities in idelalisib-refractory/intolerant CLL, and indicate that ex vivo functional profiling may stratify PI3Ki responders.
Identifiants
pubmed: 35998013
pii: 708418
doi: 10.1158/1078-0432.CCR-22-1221
pmc: PMC9588626
mid: NIHMS1833298
doi:
Substances chimiques
Antineoplastic Agents
0
Bridged Bicyclo Compounds, Heterocyclic
0
Phosphoinositide-3 Kinase Inhibitors
0
Proto-Oncogene Proteins c-bcl-2
0
Quinazolinones
0
Sulfonamides
0
Caspase 3
EC 3.4.22.-
venetoclax
N54AIC43PW
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
4444-4455Subventions
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA213442
Pays : United States
Informations de copyright
©2022 American Association for Cancer Research.
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