Biological rational for sequential targeting of Bruton tyrosine kinase and Bcl-2 to overcome CD40-induced ABT-199 resistance in mantle cell lymphoma

Oncotarget. 2015 Apr 20;6(11):8750-9. doi: 10.18632/oncotarget.3275.

Abstract

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.

Keywords: ABT-199; Bcl-2 family members; apoptosis; ibrutinib; mantle cell lymphoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agammaglobulinaemia Tyrosine Kinase
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
  • CD40 Antigens / physiology*
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / drug effects*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lymph Nodes / pathology
  • Lymphoma, Mantle-Cell / drug therapy*
  • Lymphoma, Mantle-Cell / enzymology
  • Lymphoma, Mantle-Cell / pathology
  • Molecular Targeted Therapy*
  • Myeloid Cell Leukemia Sequence 1 Protein / biosynthesis
  • Myeloid Cell Leukemia Sequence 1 Protein / genetics
  • NF-kappa B / metabolism
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasm Proteins / physiology
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / physiology
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-bcl-2 / physiology
  • Pyrazoles / pharmacology
  • Pyrazoles / therapeutic use
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use
  • RNA, Messenger / biosynthesis
  • RNA, Neoplasm / biosynthesis
  • Sulfonamides / pharmacology*
  • Tumor Microenvironment / drug effects
  • bcl-X Protein / biosynthesis
  • bcl-X Protein / genetics

Substances

  • Antineoplastic Agents
  • BCL2 protein, human
  • BCL2L1 protein, human
  • Bridged Bicyclo Compounds, Heterocyclic
  • CD40 Antigens
  • MCL1 protein, human
  • Myeloid Cell Leukemia Sequence 1 Protein
  • NF-kappa B
  • Neoplasm Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Pyrazoles
  • Pyrimidines
  • RNA, Messenger
  • RNA, Neoplasm
  • Sulfonamides
  • bcl-X Protein
  • ibrutinib
  • Protein-Tyrosine Kinases
  • Agammaglobulinaemia Tyrosine Kinase
  • BTK protein, human
  • venetoclax