• Je něco špatně v tomto záznamu ?

Cotargeting of BCL2 with Venetoclax and MCL1 with S63845 Is Synthetically Lethal In Vivo in Relapsed Mantle Cell Lymphoma

D. Prukova, L. Andera, Z. Nahacka, J. Karolova, M. Svaton, M. Klanova, O. Havranek, J. Soukup, K. Svobodova, Z. Zemanova, D. Tuskova, E. Pokorna, K. Helman, K. Forsterova, M. Pacheco-Blanco, P. Vockova, A. Berkova, E. Fronkova, M. Trneny, P. Klener,

. 2019 ; 25 (14) : 4455-4465. [pub] 20190419

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc20025772

Grantová podpora
NV17-28980A MZ0 CEP - Centrální evidence projektů

PURPOSE: Mantle cell lymphoma (MCL) is an aggressive subtype of B-cell non-Hodgkin lymphomas characterized by (over)expression of BCL2. A BCL2-targeting drug, venetoclax, has promising anticancer activity in MCL. We analyzed molecular mechanisms of venetoclax resistance in MCL cells and tested strategies to overcome it. EXPERIMENTAL DESIGN: We confirmed key roles of proapoptotic proteins BIM and NOXA in mediating venetoclax-induced cell death in MCL. Both BIM and NOXA are, however, differentially expressed in cell lines compared with primary cells. First, NOXA protein is significantly overexpressed in most MCL cell lines. Second, deletions of BIM gene harbored by three commonly used MCL cell lines (JEKO-1, MINO, and Z138) were not found by array comparative genomic hybridization using a validation set of 24 primary MCL samples. RESULTS: We demonstrated that MCL1 and NOXA play important roles in mediating resistance to venetoclax. Consequently, we tested an experimental treatment strategy based on cotargeting BCL2 with venetoclax and MCL1 with a highly specific small-molecule MCL1 inhibitor S63845. The combination of venetoclax and S63845 demonstrated synthetic lethality in vivo on a panel of five patient-derived xenografts established from patients with relapsed MCL with adverse cytogenetics. CONCLUSIONS: Our data strongly support investigation of venetoclax in combination with S63845 as an innovative treatment strategy for chemoresistant MCL patients with adverse cytogenetics in the clinical grounds.

Citace poskytuje Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc20025772
003      
CZ-PrNML
005      
20250225094716.0
007      
ta
008      
201125s2019 xxu f 000 0|eng||
009      
AR
024    7_
$a 10.1158/1078-0432.CCR-18-3275 $2 doi
035    __
$a (PubMed)31004002
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a xxu
100    1_
$a Prukova, Dana $u Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic.
245    10
$a Cotargeting of BCL2 with Venetoclax and MCL1 with S63845 Is Synthetically Lethal In Vivo in Relapsed Mantle Cell Lymphoma / $c D. Prukova, L. Andera, Z. Nahacka, J. Karolova, M. Svaton, M. Klanova, O. Havranek, J. Soukup, K. Svobodova, Z. Zemanova, D. Tuskova, E. Pokorna, K. Helman, K. Forsterova, M. Pacheco-Blanco, P. Vockova, A. Berkova, E. Fronkova, M. Trneny, P. Klener,
520    9_
$a PURPOSE: Mantle cell lymphoma (MCL) is an aggressive subtype of B-cell non-Hodgkin lymphomas characterized by (over)expression of BCL2. A BCL2-targeting drug, venetoclax, has promising anticancer activity in MCL. We analyzed molecular mechanisms of venetoclax resistance in MCL cells and tested strategies to overcome it. EXPERIMENTAL DESIGN: We confirmed key roles of proapoptotic proteins BIM and NOXA in mediating venetoclax-induced cell death in MCL. Both BIM and NOXA are, however, differentially expressed in cell lines compared with primary cells. First, NOXA protein is significantly overexpressed in most MCL cell lines. Second, deletions of BIM gene harbored by three commonly used MCL cell lines (JEKO-1, MINO, and Z138) were not found by array comparative genomic hybridization using a validation set of 24 primary MCL samples. RESULTS: We demonstrated that MCL1 and NOXA play important roles in mediating resistance to venetoclax. Consequently, we tested an experimental treatment strategy based on cotargeting BCL2 with venetoclax and MCL1 with a highly specific small-molecule MCL1 inhibitor S63845. The combination of venetoclax and S63845 demonstrated synthetic lethality in vivo on a panel of five patient-derived xenografts established from patients with relapsed MCL with adverse cytogenetics. CONCLUSIONS: Our data strongly support investigation of venetoclax in combination with S63845 as an innovative treatment strategy for chemoresistant MCL patients with adverse cytogenetics in the clinical grounds.
650    _2
$a zvířata $7 D000818
650    _2
$a antitumorózní látky $x farmakologie $7 D000970
650    _2
$a bicyklické sloučeniny heterocyklické $x farmakologie $7 D019086
650    _2
$a nádorové buněčné linie $7 D045744
650    _2
$a chemorezistence $7 D019008
650    12
$a synergismus léků $7 D004357
650    _2
$a ženské pohlaví $7 D005260
650    _2
$a lidé $7 D006801
650    _2
$a lymfom z plášťových buněk $x farmakoterapie $x metabolismus $x patologie $7 D020522
650    _2
$a myši $7 D051379
650    _2
$a myši inbrední NOD $7 D016688
650    _2
$a protein MCL-1 $x antagonisté a inhibitory $x metabolismus $7 D064549
650    _2
$a lokální recidiva nádoru $x farmakoterapie $x metabolismus $x patologie $7 D009364
650    _2
$a protoonkogenní proteiny c-bcl-2 $x antagonisté a inhibitory $x metabolismus $7 D019253
650    _2
$a pyrimidiny $x farmakologie $7 D011743
650    _2
$a sulfonamidy $x farmakologie $7 D013449
650    _2
$a thiofeny $x farmakologie $7 D013876
650    _2
$a xenogenní modely - testy antitumorózní aktivity $7 D023041
655    _2
$a časopisecké články $7 D016428
655    _2
$a práce podpořená grantem $7 D013485
700    1_
$a Andera, Ladislav $u Biocev, Institute of Biotechnology, Czech Academy of Sciences, Vestec, Czech Republic. Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czech Republic.
700    1_
$a Nahacka, Zuzana $u Biocev, Institute of Biotechnology, Czech Academy of Sciences, Vestec, Czech Republic. Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czech Republic.
700    1_
$a Karolova, Jana $u Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic. First Medical Dept., Charles University and General University Hospital, Prague, Czech Republic.
700    1_
$a Svaton, Michael $u CLIP - Childhood Leukaemia Investigation Prague, Dept. of Paediatric Haematology/Oncology, Second Faculty of Medicine and Charles University Hospital in Motol, Prague, Czech Republic.
700    1_
$a Klanova, Magdalena $u Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic. First Medical Dept., Charles University and General University Hospital, Prague, Czech Republic.
700    1_
$a Havranek, Ondrej $u First Medical Dept., Charles University and General University Hospital, Prague, Czech Republic. Biocev, First Faculty of Medicine, Charles University, Vestec, Czech Republic.
700    1_
$a Soukup, Jan, $d 1963- $u Department of Pathology and Molecular Medicine, Second Faculty of Medicine and Charles University Hospital in Motol, Prague, Czech Republic. $7 xx0140786
700    1_
$a Svobodová, Karla, $u Center for Oncocytogenetics, Institute of Medical Biochemistry and Laboratory Diagnostics, Charles University and General University Hospital, Prague, Czech Republic. $d 1986- $7 xx0276416
700    1_
$a Zemanova, Zuzana $u Center for Oncocytogenetics, Institute of Medical Biochemistry and Laboratory Diagnostics, Charles University and General University Hospital, Prague, Czech Republic.
700    1_
$a Tuskova, Diana $u Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic. First Medical Dept., Charles University and General University Hospital, Prague, Czech Republic.
700    1_
$a Pokorna, Eva $u Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic.
700    1_
$a Helman, Karel $u Faculty of Informatics and Statistics, University of Economics, Prague, Czech Republic. $7 xx0260953
700    1_
$a Forsterova, Kristina $u First Medical Dept., Charles University and General University Hospital, Prague, Czech Republic.
700    1_
$a Pacheco-Blanco, Mariana $u Biocev, First Faculty of Medicine, Charles University, Vestec, Czech Republic.
700    1_
$a Vockova, Petra $u Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic. First Medical Dept., Charles University and General University Hospital, Prague, Czech Republic.
700    1_
$a Berková, Adéla $u Center for Oncocytogenetics, Institute of Medical Biochemistry and Laboratory Diagnostics, Charles University and General University Hospital, Prague, Czech Republic. $7 xx0325890
700    1_
$a Fronkova, Eva $u CLIP - Childhood Leukaemia Investigation Prague, Dept. of Paediatric Haematology/Oncology, Second Faculty of Medicine and Charles University Hospital in Motol, Prague, Czech Republic.
700    1_
$a Trneny, Marek $u First Medical Dept., Charles University and General University Hospital, Prague, Czech Republic.
700    1_
$a Klener, Pavel $u Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic. pavel.klener@gmail.com. First Medical Dept., Charles University and General University Hospital, Prague, Czech Republic.
773    0_
$w MED00001121 $t Clinical cancer research $x 1078-0432 $g Roč. 25, č. 14 (2019), s. 4455-4465
856    41
$u https://pubmed.ncbi.nlm.nih.gov/31004002 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y a $z 0
990    __
$a 20201125 $b ABA008
991    __
$a 20250225094713 $b ABA008
999    __
$a ok $b bmc $g 1599917 $s 1116458
BAS    __
$a 3
BAS    __
$a PreBMC
BMC    __
$a 2019 $b 25 $c 14 $d 4455-4465 $e 20190419 $i 1078-0432 $m Clinical cancer research $n Clin Cancer Res $x MED00001121
GRA    __
$a NV17-28980A $p MZ0
LZP    __
$a Pubmed-20201125

Najít záznam

Citační ukazatele

Možnosti archivace