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

Abstract : Key Points • Targeting ROR1 downregulates NF-kB p65 expression and sensitizes MCL cells to BCR-or Bcl-2–targeted drugs. • Inhibition of BCR signaling by BTK-specific inhibitors such as ibrutinib impairs ROR1 levels and consecutively ROR1-targeted therapies. 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-kB p65 levels and that activation of the NF-kB 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-kB pathway activation in B-cell malignancies, this study highlights key factors that can modulate
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Submitted on : Monday, December 4, 2017 - 9:54:38 AM
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Hanna Karvonen, David Chiron, Wilhelmiina Niininen, Sara Ek, Mats Jerkeman, et al.. Crosstalk between ROR1 and BCR pathways defines novel treatment strategies in mantle cell lymphoma. Blood, American Society of Hematology, 2017, 1 (24), pp.2257-2268. ⟨10.1182/bloodadvances.2017010215⟩. ⟨inserm-01654519⟩



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