title: Dual targeting of MCL1 and NOXA as effective strategy for treatment of mantle cell lymphoma.
abstract: Imbalances in the composition of BCL2 family proteins contribute to tumourigenesis and therapy resistance of mantle cell lymphoma (MCL), making these proteins attractive therapy targets. We studied the efficiency of dual targeting the NOXA/MCL1 axis by combining fatty acid synthase inhibitors (NOXA stabilization) with the CDK inhibitor Dinaciclib (MCL1 reduction). This combination synergistically induced apoptosis in cell lines and primary MCL cells and led to almost complete inhibition of tumour progression in a mouse model. Apoptosis was NOXA-dependent and correlated with the NOXA/MCL1 ratio, highlighting the importance of the NOXA/MCL1 balance for effective cell death induction in MCL.
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology and University of Tuebingen, Stuttgart, Germany.|Department of Haematology and Oncology, Robert-Bosch-Hospital, Stuttgart, Germany.|Haematopathology Unit, Hospital Clínic - Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Höring
authors.affiliation: Haematopathology Unit, Hospital Clínic - Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain.
authors.forename: Arnau
authors.initials: A
authors.lastname: Montraveta
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology and University of Tuebingen, Stuttgart, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Heine
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology and University of Tuebingen, Stuttgart, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Kleih
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology and University of Tuebingen, Stuttgart, Germany.
authors.forename: Lea
authors.initials: L
authors.lastname: Schaaf
authors.affiliation: Department of Haematology and Oncology, Robert-Bosch-Hospital, Stuttgart, Germany.
authors.forename: Matthias C
authors.initials: MC
authors.lastname: Vöhringer
authors.affiliation: Haematopathology Unit, Hospital Clínic - Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Esteve-Arenys
authors.affiliation: Haematopathology Unit, Hospital Clínic - Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain.
authors.forename: Gael
authors.initials: G
authors.lastname: Roué
authors.affiliation: Haematopathology Unit, Hospital Clínic - Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain.
authors.forename: Dolors
authors.initials: D
authors.lastname: Colomer
authors.affiliation: Haematopathology Unit, Hospital Clínic - Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain.
authors.forename: Elias
authors.initials: E
authors.lastname: Campo
authors.affiliation: Department of Clinical Pathology, Robert-Bosch-Hospital, Stuttgart, Germany.
authors.forename: German
authors.initials: G
authors.lastname: Ott
authors.affiliation: Department of Haematology and Oncology, Robert-Bosch-Hospital, Stuttgart, Germany.
authors.forename: Walter E
authors.initials: WE
authors.lastname: Aulitzky
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology and University of Tuebingen, Stuttgart, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: van der Kuip
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D045744:Cell Line, Tumor; D003497:Cyclic N-Oxides; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007212:Indolizines; D007783:Lactones / Q000494:pharmacology; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy*; D016513:Mice, SCID; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors*; D000077403:Orlistat; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D011726:Pyridinium Compounds / Q000494:pharmacology
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D003497:Cyclic N-Oxides; D004791:Enzyme Inhibitors; D007212:Indolizines; D007783:Lactones; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D011726:Pyridinium Compounds; C553669:dinaciclib; D000077403:Orlistat; D018844:Cyclin-Dependent Kinases
keywords: Dinaciclib; FASNi; MCL1; NOXA; mantle cell lymphoma