Dual targeting of MCL1 and NOXA as effective strategy for treatment of mantle cell lymphoma

Summary 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 inhibitor...

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Bibliographic Details
Published in:British journal of haematology 2017-05, Vol.177 (4), p.557-561
Main Authors: Höring, Elisabeth, Montraveta, Arnau, Heine, Simon, Kleih, Markus, Schaaf, Lea, Vöhringer, Matthias C., Esteve‐Arenys, Anna, Roué, Gael, Colomer, Dolors, Campo, Elias, Ott, German, Aulitzky, Walter E., Kuip, Heiko
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Apoptosis - drug effects
Bridged Bicyclo Compounds, Heterocyclic - pharmacology
Cell death
Cell Line, Tumor
Cyclin-Dependent Kinases - antagonists & inhibitors
Dinaciclib
Enzyme Inhibitors - therapeutic use
FASNi
Fatty-acid synthase
Female
Hematology
Humans
Lactones - pharmacology
Lymphoma
Lymphoma, Mantle-Cell - drug therapy
Mantle cell lymphoma
Mcl-1 protein
MCL1
Mice, SCID
Myeloid Cell Leukemia Sequence 1 Protein - antagonists & inhibitors
NOXA
Proteins
Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors
Pyridinium Compounds - pharmacology
Tumorigenesis
Tumors
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Summary:Summary 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.
ISSN:0007-1048
1365-2141
DOI:10.1111/bjh.14571