Biological rational for sequential targeting of Bruton tyrosine kinase and Bcl-2 to overcome CD40-induced ABT-199 resistance in mantle cell lymphoma.
The aggressive biological behavior of mantle cell lymphoma (MCL) and its short response to current treatment highlight a great need for better rational therapy. Herein, we investigate the ability of ABT-199, the Bcl-2-selective BH3 mimetic, to kill MCL cells. Among MCL cell lines tested (n = 8), only three were sensitive (LD50 < 200 nM). In contrast, all primary MCL samples tested (n = 11) were highly sensitive to ABT-199 (LD50 < 10 nM). Mcl-1 and Bcl-xL both confer resistance to ABT-199-specific killing and BCL2/(BCLXL+MCL1) mRNA ratio is a strong predictor of sensitivity. By mimicking the microenvironment through CD40 stimulation, we show that ABT-199 sensitivity is impaired through activation of NF-kB pathway and Bcl-x(L) up-regulation. We further demonstrate that resistance is rapidly lost when MCL cells detach from CD40L-expressing fibroblasts. It has been reported that ibrutinib induces lymphocytosis in vivo holding off malignant cells from their protective microenvironment. We show here for two patients undergoing ibrutinib therapy that mobilized MCL cells are highly sensitive to ABT-199. These results provide evidence that in situ ABT-199 resistance can be overcome when MCL cells escape from the lymph nodes. Altogether, our data support the clinical application of ABT-199 therapy both as a single agent and in sequential combination with BTK inhibitors.
['Chiron|David|D|', 'Dousset|Christelle|C|', 'Brosseau|Carole|C|', 'Touzeau|Cyrille|C|', 'Maïga|Sophie|S|', 'Moreau|Philippe|P|', 'Pellat-Deceunynck|Catherine|C|', 'Le Gouill|Steven|S|', 'Amiot|Martine|M|']
D000225:Adenine D000077329:Agammaglobulinaemia Tyrosine Kinase D000970:Antineoplastic Agents D017209:Apoptosis D019086:Bridged Bicyclo Compounds, Heterocyclic D019013:CD40 Antigens D045744:Cell Line, Tumor D019008:Drug Resistance, Neoplasm D015972:Gene Expression Regulation, Neoplastic D006801:Humans D008198:Lymph Nodes D020522:Lymphoma, Mantle-Cell D058990:Molecular Targeted Therapy D064549:Myeloid Cell Leukemia Sequence 1 Protein D016328:NF-kappa B D009363:Neoplasm Proteins D010880:Piperidines D011505:Protein-Tyrosine Kinases D019253:Proto-Oncogene Proteins c-bcl-2 D011720:Pyrazoles D011743:Pyrimidines D012333:RNA, Messenger D012334:RNA, Neoplasm D013449:Sulfonamides D059016:Tumor Microenvironment D051020:bcl-X Protein
ABT-199 mantle cell lymphoma ibrutinib Bcl-2 family members apoptosis