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Blood Adv. 2017 Nov 9;1(24):2257-2268. doi: 10.1182/bloodadvances.2017010215. eCollection 2017 Nov 14.

Crosstalk between ROR1 and BCR pathways defines novel treatment strategies in mantle cell lymphoma.

Author information

1
BioMediTech Institute and.
2
Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.
3
Centre de Recherche en Cancérologie et Immunologie Nantes Angers, INSERM, Centre National de la Recherche Scientifique, Université de Nantes, Centre Hospitalier Universitaire de Nantes, Nantes, France.
4
Department of Immunotechnology, Faculty of Engineering, and.
5
Department of Oncology and Pathology, Institute of Clinical Sciences, Lund University, Lund, Sweden.
6
Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland; and.
7
Science for Life Laboratory, Department of Oncology and Pathology, Karolinska Institutet, Solna, Sweden.

Abstract

Mantle cell lymphoma (MCL) is an aggressive form of non-Hodgkin B-cell lymphoma with poor prognosis due to drug resistance. Introduction of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib has markedly improved MCL therapy outcome, but drug resistance remains a challenge. The selective cell-surface expression of oncogenic receptor tyrosine kinase-like orphan receptor 1 (ROR1) pseudokinase in hematological malignancies has made this receptor a promising candidate for targeted therapy. We sought to identify the molecular mechanism underlying divergent ROR1-mediated apoptotic responses in MCL cell lines and primary samples. We show that targeting ROR1 expression resulted in downregulation of NF-κB p65 levels and that activation of the NF-κB pathway can antagonize ROR1-mediated apoptotic responses. High-throughput drug-sensitivity testing of MCL cells before and after ROR1 targeting revealed synergistic effects between cotargeting of ROR1 and the B-cell antigen receptor (BCR) or Bcl-2 family, underlining the high potential for ROR1-targeted therapies in overcoming MCL drug resistance. However, inhibition of the BCR pathway by targeted drugs such as ibrutinib can impair ROR1 expression and consequently ROR1-targeted treatments, underscoring the importance of inhibiting both pathways to augment cancer cell killing. Considering the central role of NF-κB pathway activation in B-cell malignancies, this study highlights key factors that can modulate ROR1-targeted treatments in hematological cancers.

Conflict of interest statement

Conflict-of-interest disclosure: The authors declare no competing financial interests.

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