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Sensitivity to PI3K and AKT inhibitors is mediated by divergent molecular mechanisms in subtypes of DLBCL.
- Source :
-
Blood [Blood] 2017 Jul 20; Vol. 130 (3), pp. 310-322. Date of Electronic Publication: 2017 Feb 15. - Publication Year :
- 2017
-
Abstract
- Activated B-cell-like (ABC) and germinal center B-cell-like diffuse large B-cell lymphoma (DLBCL) represent the 2 major molecular DLBCL subtypes. They are characterized by differences in clinical course and by divergent addiction to oncogenic pathways. To determine activity of novel compounds in these 2 subtypes, we conducted an unbiased pharmacologic in vitro screen. The phosphatidylinositol-3-kinase (PI3K) α/δ (PI3Kα/δ) inhibitor AZD8835 showed marked potency in ABC DLBCL models, whereas the protein kinase B (AKT) inhibitor AZD5363 induced apoptosis in PTEN-deficient DLBCLs irrespective of their molecular subtype. These in vitro results were confirmed in various cell line xenograft and patient-derived xenograft mouse models in vivo. Treatment with AZD8835 induced inhibition of nuclear factor κB signaling, prompting us to combine AZD8835 with the Bruton's tyrosine kinase inhibitor ibrutinib. This combination was synergistic and effective both in vitro and in vivo. In contrast, the AKT inhibitor AZD5363 was effective in PTEN-deficient DLBCLs through downregulation of the oncogenic transcription factor MYC. Collectively, our data suggest that patients should be stratified according to their oncogenic dependencies when treated with PI3K and AKT inhibitors.<br /> (© 2017 by The American Society of Hematology.)
- Subjects :
- Adenine analogs & derivatives
Agammaglobulinaemia Tyrosine Kinase
Animals
Apoptosis drug effects
Drug Combinations
Drug Screening Assays, Antitumor
Drug Synergism
Humans
Lymphoma, Large B-Cell, Diffuse classification
Lymphoma, Large B-Cell, Diffuse genetics
Lymphoma, Large B-Cell, Diffuse pathology
Mice
NF-kappa B antagonists & inhibitors
NF-kappa B genetics
NF-kappa B metabolism
Organ Specificity
PTEN Phosphohydrolase deficiency
PTEN Phosphohydrolase genetics
Phosphatidylinositol 3-Kinases genetics
Phosphatidylinositol 3-Kinases metabolism
Phosphoinositide-3 Kinase Inhibitors
Protein-Tyrosine Kinases antagonists & inhibitors
Protein-Tyrosine Kinases genetics
Protein-Tyrosine Kinases metabolism
Proto-Oncogene Proteins c-akt antagonists & inhibitors
Proto-Oncogene Proteins c-akt genetics
Proto-Oncogene Proteins c-akt metabolism
Proto-Oncogene Proteins c-myc antagonists & inhibitors
Proto-Oncogene Proteins c-myc genetics
Proto-Oncogene Proteins c-myc metabolism
Signal Transduction
Xenograft Model Antitumor Assays
Antineoplastic Agents pharmacology
Gene Expression Regulation, Neoplastic
Lymphoma, Large B-Cell, Diffuse drug therapy
Oxadiazoles pharmacology
Piperidines pharmacology
Protein Kinase Inhibitors pharmacology
Pyrazoles pharmacology
Pyrimidines pharmacology
Pyrroles pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0020
- Volume :
- 130
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 28202458
- Full Text :
- https://doi.org/10.1182/blood-2016-12-758599