Detail
Article
Online article
FT
Medvik - BMC
  • Something wrong with this record ?

Cyclin dependent kinase 4/6 inhibitor palbociclib synergizes with BCL2 inhibitor venetoclax in experimental models of mantle cell lymphoma without RB1 deletion

D. Malarikova, R. Jorda, K. Kupcova, J. Senavova, A. Dolnikova, E. Pokorna, D. Kazantsev, K. Nozickova, D. Sovilj, C. Bellanger, D. Chiron, L. Andera, V. Krystof, M. Strnad, K. Helman, M. Klanova, M. Trneny, O. Havranek, P. Klener

. 2024 ; 13 (1) : 34. [pub] 20240325

Status not-indexed Language English Country England, Great Britain

Document type Letter

Persistent link   https://www.medvik.cz/link/bmc24005545

Grant support
GA19-08772S Grantová Agentura České Republiky
GA23-05474S Grantová Agentura České Republiky
PRIMUS 19/MED/07 Grantová Agentura, Univerzita Karlova
PRIMUS 17/MED/09 Grantová Agentura, Univerzita Karlova
UNCE/MED/016 Grantová Agentura, Univerzita Karlova
AZV NU21-03-00386 Ministerstvo Zdravotnictví Ceské Republiky
LX22NPO5102 National Institute for Cancer Research (EXCELES)

BACKGROUND: Mantle cell lymphoma (MCL) is a chronically relapsing malignancy with deregulated cell cycle progression. We analyzed efficacy, mode of action, and predictive markers of susceptibility to palbociclib, an approved CDK 4/6 inhibitor, and its combination with venetoclax, a BCL2 inhibitor. METHODS: A panel of nine MCL cell lines were used for in vitro experiments. Four patient derived xenografts (PDX) obtained from patients with chemotherapy and ibrutinib-refractory MCL were used for in vivo proof-of-concept studies. Changes of the mitochondrial membrane potential, energy-metabolic pathways, AKT activity, and pro-apoptotic priming of MCL cells were evaluated by JC-1 staining, Seahorse XF analyser, genetically encoded fluorescent AKT reporter, and BH3 profiling, respectively. MCL clones with gene knockout or transgenic (over)expression of CDKN2A, MYC, CDK4, and RB1 were used to estimate impact of these aberrations on sensitivity to palbociclib, and venetoclax. RESULTS: Co-targeting MCL cells with palbociclib and venetoclax induced cytotoxic synergy in vitro and in vivo. Molecular mechanisms responsible for the observed synthetic lethality comprised palbociclib-mediated downregulation of anti-apoptotic MCL1, increased levels of proapoptotic BIM bound on both BCL2, and BCL-XL and increased pro-apoptotic priming of MCL cells mediated by BCL2-independent mechanisms, predominantly palbociclib-triggered metabolic and mitochondrial stress. Loss of RB1 resulted in palbociclib resistance, while deletion of CDKN2A or overexpression of CDK4, and MYC genes did not change sensitivity to palbociclib. CONCLUSIONS: Our data strongly support investigation of the chemotherapy-free palbociclib and venetoclax combination as an innovative treatment strategy for post-ibrutinib MCL patients without RB1 deletion.

References provided by Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc24005545
003      
CZ-PrNML
005      
20250521101650.0
007      
ta
008      
240405s2024 enk f 000 0|eng||
009      
AR
024    7_
$a 10.1186/s40164-024-00499-2 $2 doi
035    __
$a (PubMed)38528594
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a enk
100    1_
$a Maláriková, Diana $u Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic $u First Department of Internal Medicine - Hematology, First Faculty of Medicine, General University Hospital, Charles University, Prague, Czech Republic $7 xx0332458
245    10
$a Cyclin dependent kinase 4/6 inhibitor palbociclib synergizes with BCL2 inhibitor venetoclax in experimental models of mantle cell lymphoma without RB1 deletion / $c D. Malarikova, R. Jorda, K. Kupcova, J. Senavova, A. Dolnikova, E. Pokorna, D. Kazantsev, K. Nozickova, D. Sovilj, C. Bellanger, D. Chiron, L. Andera, V. Krystof, M. Strnad, K. Helman, M. Klanova, M. Trneny, O. Havranek, P. Klener
520    9_
$a BACKGROUND: Mantle cell lymphoma (MCL) is a chronically relapsing malignancy with deregulated cell cycle progression. We analyzed efficacy, mode of action, and predictive markers of susceptibility to palbociclib, an approved CDK 4/6 inhibitor, and its combination with venetoclax, a BCL2 inhibitor. METHODS: A panel of nine MCL cell lines were used for in vitro experiments. Four patient derived xenografts (PDX) obtained from patients with chemotherapy and ibrutinib-refractory MCL were used for in vivo proof-of-concept studies. Changes of the mitochondrial membrane potential, energy-metabolic pathways, AKT activity, and pro-apoptotic priming of MCL cells were evaluated by JC-1 staining, Seahorse XF analyser, genetically encoded fluorescent AKT reporter, and BH3 profiling, respectively. MCL clones with gene knockout or transgenic (over)expression of CDKN2A, MYC, CDK4, and RB1 were used to estimate impact of these aberrations on sensitivity to palbociclib, and venetoclax. RESULTS: Co-targeting MCL cells with palbociclib and venetoclax induced cytotoxic synergy in vitro and in vivo. Molecular mechanisms responsible for the observed synthetic lethality comprised palbociclib-mediated downregulation of anti-apoptotic MCL1, increased levels of proapoptotic BIM bound on both BCL2, and BCL-XL and increased pro-apoptotic priming of MCL cells mediated by BCL2-independent mechanisms, predominantly palbociclib-triggered metabolic and mitochondrial stress. Loss of RB1 resulted in palbociclib resistance, while deletion of CDKN2A or overexpression of CDK4, and MYC genes did not change sensitivity to palbociclib. CONCLUSIONS: Our data strongly support investigation of the chemotherapy-free palbociclib and venetoclax combination as an innovative treatment strategy for post-ibrutinib MCL patients without RB1 deletion.
590    __
$a NEINDEXOVÁNO
655    _2
$a dopisy $7 D016422
700    1_
$a Jorda, Radek $u Department of Experimental Biology, Faculty of Science, Palacky University Olomouc, Olomouc, Czech Republic
700    1_
$a Kupcová, Kristýna $u First Department of Internal Medicine - Hematology, First Faculty of Medicine, General University Hospital, Charles University, Prague, Czech Republic $u BIOCEV LF1 - Biotechnology and Biomedicine Centre, First Faculty of Medicine, Charles University, Prague, Czech Republic $7 xx0328095
700    1_
$a Senavova, Jana $u First Department of Internal Medicine - Hematology, First Faculty of Medicine, General University Hospital, Charles University, Prague, Czech Republic $u BIOCEV LF1 - Biotechnology and Biomedicine Centre, First Faculty of Medicine, Charles University, Prague, Czech Republic
700    1_
$a Dolnikova, Alexandra $u Institute of Pathological Physiology, First Faculty of Medicine, Charles University, 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 Kazantsev, Dmitry $u Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic
700    1_
$a Nozickova, Kristina $u Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic
700    1_
$a Sovilj, Dana $u Institute of Biotechnology, Czech Academy of Sciences, Prague, Czech Republic
700    1_
$a Bellanger, Celine $u Integrated Research Center in Immunology and Oncology, CRCI2NA, Nantes University, Nantes, France
700    1_
$a Chiron, David $u Integrated Research Center in Immunology and Oncology, CRCI2NA, Nantes University, Nantes, France
700    1_
$a Andera, Ladislav $u BIOCEV LF1 - Biotechnology and Biomedicine Centre, First Faculty of Medicine, Charles University, Prague, Czech Republic $u Institute of Biotechnology, Czech Academy of Sciences, Prague, Czech Republic $u Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czech Republic
700    1_
$a Krystof, Vladimir $u Department of Experimental Biology, Faculty of Science, Palacky University Olomouc, Olomouc, Czech Republic
700    1_
$a Strnad, Miroslav $u Laboratory of Growth Regulators, Palacky University Olomouc and Institute of Experimental Botany, The Czech Academy of Sciences, Olomouc, Czech Republic
700    1_
$a Helman, Karel $u Faculty of Informatics and Statistics, Prague University of Economics and Business, Prague, Czech Republic
700    1_
$a Klanova, Magdalena $u Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic $u First Department of Internal Medicine - Hematology, First Faculty of Medicine, General University Hospital, Charles University, Prague, Czech Republic
700    1_
$a Trneny, Marek $u First Department of Internal Medicine - Hematology, First Faculty of Medicine, General University Hospital, Charles University, Prague, Czech Republic
700    1_
$a Havranek, Ondrej $u First Department of Internal Medicine - Hematology, First Faculty of Medicine, General University Hospital, Charles University, Prague, Czech Republic $u BIOCEV LF1 - Biotechnology and Biomedicine Centre, First Faculty of Medicine, Charles University, Prague, Czech Republic
700    1_
$a Klener, Pavel $u Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic. pavel.klener2@lf1.cuni.cz $u First Department of Internal Medicine - Hematology, First Faculty of Medicine, General University Hospital, Charles University, Prague, Czech Republic. pavel.klener2@lf1.cuni.cz
773    0_
$w MED00213965 $t Experimental hematology & oncology $x 2162-3619 $g Roč. 13, č. 1 (2024), s. 34
856    41
$u https://pubmed.ncbi.nlm.nih.gov/38528594 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y - $z 0
990    __
$a 20240405 $b ABA008
991    __
$a 20250521101648 $b ABA008
999    __
$a ok $b bmc $g 2075951 $s 1215307
BAS    __
$a 3
BAS    __
$a PreBMC-PubMed-not-MEDLINE
BMC    __
$a 2024 $b 13 $c 1 $d 34 $e 20240325 $i 2162-3619 $m Experimental hematology & oncology $n Exp Hematol Oncol $x MED00213965
GRA    __
$a GA19-08772S $p Grantová Agentura České Republiky
GRA    __
$a GA23-05474S $p Grantová Agentura České Republiky
GRA    __
$a PRIMUS 19/MED/07 $p Grantová Agentura, Univerzita Karlova
GRA    __
$a PRIMUS 17/MED/09 $p Grantová Agentura, Univerzita Karlova
GRA    __
$a UNCE/MED/016 $p Grantová Agentura, Univerzita Karlova
GRA    __
$a AZV NU21-03-00386 $p Ministerstvo Zdravotnictví Ceské Republiky
GRA    __
$a LX22NPO5102 $p National Institute for Cancer Research (EXCELES)
LZP    __
$a Pubmed-20240405

Find record

Citation metrics

Archiving options