-
Je něco špatně v tomto záznamu ?
Sensitivity to PI3K and AKT inhibitors is mediated by divergent molecular mechanisms in subtypes of DLBCL
T. Erdmann, P. Klener, JT. Lynch, M. Grau, P. Vočková, J. Molinsky, D. Tuskova, K. Hudson, UM. Polanska, M. Grondine, M. Mayo, B. Dai, M. Pfeifer, K. Erdmann, D. Schwammbach, M. Zapukhlyak, AM. Staiger, G. Ott, WE. Berdel, BR. Davies, F....
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články
Grantová podpora
NV15-27757A
MZ0
CEP - Centrální evidence projektů
Digitální knihovna NLK
Plný text - Článek
Zdroj
NLK
Free Medical Journals
od 1946 do Před 1 rokem
Freely Accessible Science Journals
od 1946 do Před 1 rokem
Open Access Digital Library
od 1946-01-01
Open Access Digital Library
od 1946-01-01
ROAD: Directory of Open Access Scholarly Resources
- MeSH
- apoptóza účinky léků MeSH
- difúzní velkobuněčný B-lymfom klasifikace farmakoterapie genetika patologie MeSH
- fixní kombinace léků MeSH
- fosfatidylinositol-3-kinasy genetika metabolismus MeSH
- fosfohydroláza PTEN nedostatek genetika MeSH
- inhibitory fosfoinositid-3-kinasy MeSH
- inhibitory proteinkinas farmakologie MeSH
- lidé MeSH
- myši MeSH
- NF-kappa B antagonisté a inhibitory genetika metabolismus MeSH
- orgánová specificita MeSH
- oxadiazoly farmakologie MeSH
- piperidiny farmakologie MeSH
- protinádorové látky farmakologie MeSH
- protoonkogenní proteiny c-akt antagonisté a inhibitory genetika metabolismus MeSH
- protoonkogenní proteiny c-myc antagonisté a inhibitory genetika metabolismus MeSH
- pyrazoly farmakologie MeSH
- pyrimidiny farmakologie MeSH
- pyrroly farmakologie MeSH
- regulace genové exprese u nádorů * MeSH
- screeningové testy protinádorových léčiv MeSH
- signální transdukce MeSH
- synergismus léků MeSH
- tyrosinkinasy antagonisté a inhibitory genetika metabolismus MeSH
- xenogenní modely - testy protinádorové aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
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.
Department of Clinical Pathology Robert Bosch Hospital Stuttgart Germany
Department of Physics Philipps University Marburg Germany
Division of Cancer Department of Surgery and Cancer Imperial College London United Kingdom
Citace poskytuje Crossref.org
- 000
- 00000naa a2200000 a 4500
- 001
- bmc17031040
- 003
- CZ-PrNML
- 005
- 20201019150449.0
- 007
- ta
- 008
- 171025s2017 xxu f 000 0|eng||
- 009
- AR
- 024 7_
- $a 10.1182/blood-2016-12-758599 $2 doi
- 035 __
- $a (PubMed)28202458
- 040 __
- $a ABA008 $b cze $d ABA008 $e AACR2
- 041 0_
- $a eng
- 044 __
- $a xxu
- 100 1_
- $a Erdmann, Tabea $u Translational Oncology, University Hospital Münster, Münster, Germany. Cluster of Excellence EXC 1003, Cells in Motion, Münster, Germany. Fachbereich Chemie und Pharmazie, University of Münster, Münster, Germany.
- 245 10
- $a Sensitivity to PI3K and AKT inhibitors is mediated by divergent molecular mechanisms in subtypes of DLBCL / $c T. Erdmann, P. Klener, JT. Lynch, M. Grau, P. Vočková, J. Molinsky, D. Tuskova, K. Hudson, UM. Polanska, M. Grondine, M. Mayo, B. Dai, M. Pfeifer, K. Erdmann, D. Schwammbach, M. Zapukhlyak, AM. Staiger, G. Ott, WE. Berdel, BR. Davies, F. Cruzalegui, M. Trneny, P. Lenz, ST. Barry, G. Lenz,
- 520 9_
- $a 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.
- 650 _2
- $a zvířata $7 D000818
- 650 _2
- $a protinádorové látky $x farmakologie $7 D000970
- 650 _2
- $a apoptóza $x účinky léků $7 D017209
- 650 _2
- $a fixní kombinace léků $7 D004338
- 650 _2
- $a screeningové testy protinádorových léčiv $7 D004354
- 650 _2
- $a synergismus léků $7 D004357
- 650 12
- $a regulace genové exprese u nádorů $7 D015972
- 650 _2
- $a lidé $7 D006801
- 650 _2
- $a difúzní velkobuněčný B-lymfom $x klasifikace $x farmakoterapie $x genetika $x patologie $7 D016403
- 650 _2
- $a myši $7 D051379
- 650 _2
- $a NF-kappa B $x antagonisté a inhibitory $x genetika $x metabolismus $7 D016328
- 650 _2
- $a orgánová specificita $7 D009928
- 650 _2
- $a oxadiazoly $x farmakologie $7 D010069
- 650 _2
- $a fosfohydroláza PTEN $x nedostatek $x genetika $7 D051059
- 650 _2
- $a fosfatidylinositol-3-kinasy $x genetika $x metabolismus $7 D019869
- 650 _2
- $a piperidiny $x farmakologie $7 D010880
- 650 _2
- $a inhibitory proteinkinas $x farmakologie $7 D047428
- 650 _2
- $a tyrosinkinasy $x antagonisté a inhibitory $x genetika $x metabolismus $7 D011505
- 650 _2
- $a protoonkogenní proteiny c-akt $x antagonisté a inhibitory $x genetika $x metabolismus $7 D051057
- 650 _2
- $a protoonkogenní proteiny c-myc $x antagonisté a inhibitory $x genetika $x metabolismus $7 D016271
- 650 _2
- $a pyrazoly $x farmakologie $7 D011720
- 650 _2
- $a pyrimidiny $x farmakologie $7 D011743
- 650 _2
- $a pyrroly $x farmakologie $7 D011758
- 650 _2
- $a signální transdukce $7 D015398
- 650 _2
- $a xenogenní modely - testy protinádorové aktivity $7 D023041
- 650 _2
- $a inhibitory fosfoinositid-3-kinasy $7 D000081082
- 655 _2
- $a časopisecké články $7 D016428
- 700 1_
- $a Klener, Pavel $u Institute of Pathological Physiology, First Faculty of Medicine, Charles University Prague, Prague, Czech Republic. First Medical Department, Department of Hematology, Charles University General Hospital Prague, Prague, Czech Republic.
- 700 1_
- $a Lynch, James T $u Innovative Medicines and Early Development (IMED) Oncology AstraZeneca, Li Ka Shing Centre, Cambridge, United Kingdom.
- 700 1_
- $a Grau, Michael $u Translational Oncology, University Hospital Münster, Münster, Germany. Cluster of Excellence EXC 1003, Cells in Motion, Münster, Germany.
- 700 1_
- $a Vočková, Petra $u Institute of Pathological Physiology, First Faculty of Medicine, Charles University Prague, Prague, Czech Republic. First Medical Department, Department of Hematology, Charles University General Hospital Prague, Prague, Czech Republic.
- 700 1_
- $a Molinsky, Jan $u Institute of Pathological Physiology, First Faculty of Medicine, Charles University Prague, Prague, Czech Republic. First Medical Department, Department of Hematology, Charles University General Hospital Prague, Prague, Czech Republic.
- 700 1_
- $a Tuskova, Diana $u Institute of Pathological Physiology, First Faculty of Medicine, Charles University Prague, Prague, Czech Republic. First Medical Department, Department of Hematology, Charles University General Hospital Prague, Prague, Czech Republic.
- 700 1_
- $a Hudson, Kevin $u Innovative Medicines and Early Development (IMED) Oncology AstraZeneca, Li Ka Shing Centre, Cambridge, United Kingdom.
- 700 1_
- $a Polanska, Urszula M $u Innovative Medicines and Early Development (IMED) Oncology AstraZeneca, Li Ka Shing Centre, Cambridge, United Kingdom.
- 700 1_
- $a Grondine, Michael $u IMED Oncology AstraZeneca, Gatehouse Park, Boston, MA.
- 700 1_
- $a Mayo, Michele $u IMED Oncology AstraZeneca, Gatehouse Park, Boston, MA.
- 700 1_
- $a Dai, Beiying $u Translational Oncology, University Hospital Münster, Münster, Germany. Cluster of Excellence EXC 1003, Cells in Motion, Münster, Germany.
- 700 1_
- $a Pfeifer, Matthias $u Division of Cancer, Department of Surgery & Cancer, Imperial College, London, United Kingdom.
- 700 1_
- $a Erdmann, Kristian $u Translational Oncology, University Hospital Münster, Münster, Germany. Cluster of Excellence EXC 1003, Cells in Motion, Münster, Germany.
- 700 1_
- $a Schwammbach, Daniela $u Translational Oncology, University Hospital Münster, Münster, Germany. Cluster of Excellence EXC 1003, Cells in Motion, Münster, Germany.
- 700 1_
- $a Zapukhlyak, Myroslav $u Translational Oncology, University Hospital Münster, Münster, Germany. Cluster of Excellence EXC 1003, Cells in Motion, Münster, Germany.
- 700 1_
- $a Staiger, Annette M $u Department of Clinical Pathology, Robert-Bosch-Hospital, Stuttgart, Germany. Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
- 700 1_
- $a Ott, German $u Department of Clinical Pathology, Robert-Bosch-Hospital, Stuttgart, Germany.
- 700 1_
- $a Berdel, Wolfgang E $u Cluster of Excellence EXC 1003, Cells in Motion, Münster, Germany. Department of Medicine A, Hematology, Oncology, and Pneumology, University Hospital Münster, Münster, Germany; and.
- 700 1_
- $a Davies, Barry R $u Innovative Medicines and Early Development (IMED) Oncology AstraZeneca, Li Ka Shing Centre, Cambridge, United Kingdom.
- 700 1_
- $a Cruzalegui, Francisco $u Innovative Medicines and Early Development (IMED) Oncology AstraZeneca, Li Ka Shing Centre, Cambridge, United Kingdom.
- 700 1_
- $a Trneny, Marek $u Institute of Pathological Physiology, First Faculty of Medicine, Charles University Prague, Prague, Czech Republic. First Medical Department, Department of Hematology, Charles University General Hospital Prague, Prague, Czech Republic.
- 700 1_
- $a Lenz, Peter $u Department of Physics, Philipps University, Marburg, Germany.
- 700 1_
- $a Barry, Simon T $u Innovative Medicines and Early Development (IMED) Oncology AstraZeneca, Li Ka Shing Centre, Cambridge, United Kingdom.
- 700 1_
- $a Lenz, Georg $u Translational Oncology, University Hospital Münster, Münster, Germany. Cluster of Excellence EXC 1003, Cells in Motion, Münster, Germany. Department of Medicine A, Hematology, Oncology, and Pneumology, University Hospital Münster, Münster, Germany; and.
- 773 0_
- $w MED00000807 $t Blood $x 1528-0020 $g Roč. 130, č. 3 (2017), s. 310-322
- 856 41
- $u https://pubmed.ncbi.nlm.nih.gov/28202458 $y Pubmed
- 910 __
- $a ABA008 $b sig $c sign $y a $z 0
- 990 __
- $a 20171025 $b ABA008
- 991 __
- $a 20201019150449 $b ABA008
- 999 __
- $a ok $b bmc $g 1254633 $s 992067
- BAS __
- $a 3
- BAS __
- $a PreBMC
- BMC __
- $a 2017 $b 130 $c 3 $d 310-322 $e 20170215 $i 1528-0020 $m Blood $n Blood $x MED00000807
- GRA __
- $a NV15-27757A $p MZ0
- LZP __
- $a Pubmed-20171025
