1. Dual targeting of MCL1 and NOXA as effective strategy for treatment of mantle cell lymphoma
- Author
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Simon Heine, Walter E. Aulitzky, Lea Schaaf, Gaël Roué, Matthias Vöhringer, Dolors Colomer, Elias Campo, Anna Esteve-Arenys, Arnau Montraveta, Markus Kleih, Elisabeth Höring, German Ott, and Heiko van der Kuip
- Subjects
0301 basic medicine ,Dual targeting ,Apoptosis ,Pyridinium Compounds ,Lymphoma, Mantle-Cell ,Mice, SCID ,Cyclic N-Oxides ,Lactones ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Cell Line, Tumor ,hemic and lymphatic diseases ,medicine ,Animals ,Humans ,MCL1 ,Enzyme Inhibitors ,Dinaciclib ,Orlistat ,biology ,Indolizines ,Hematology ,Bridged Bicyclo Compounds, Heterocyclic ,medicine.disease ,Cyclin-Dependent Kinases ,Cell biology ,Fatty acid synthase ,030104 developmental biology ,Cell Death Induction ,Proto-Oncogene Proteins c-bcl-2 ,chemistry ,030220 oncology & carcinogenesis ,biology.protein ,Myeloid Cell Leukemia Sequence 1 Protein ,Female ,Mantle cell lymphoma ,CDK inhibitor - 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.
- Published
- 2017