Biological rational for sequential targeting of Bruton tyrosine kinase and Bcl-2 to overcome CD40-induced ABT-199 resistance in mantle cell lymphoma
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David Chiron1, Christelle Dousset1,2,3,*, Carole Brosseau1,*, Cyrille Touzeau1,2, Sophie Maïga1,2, Philippe Moreau1,2, Catherine Pellat-Deceunynck1,2, Steven Le Gouill1,2,3, Martine Amiot1,2
1INSERM, UMR892 - CNRS, UMR 6299, Université de Nantes, France
2Service d’Hématologie Clinique, Unité d’Investigation Clinique, Centre Hospitalier Universitaire de Nantes, France
3CIC, INSERM, Nantes, France
*These authors have contributed equally to this work
Martine Amiot, e-mail: [email protected]
Keywords: ABT-199, mantle cell lymphoma, apoptosis, Bcl-2 family members, ibrutinib
Received: February 04, 2015 Accepted: February 08, 2015 Published: March 05, 2015
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-xL 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.
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