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

Karvonen, Hanna ; Chiron, David ; Niininen, Wilhelmiina ; Ek, Sara LU ; Jerkeman, Mats LU ; Moradi, Elaheh ; Nykter, Matti ; Heckman, Caroline A. ; Kallioniemi, Olli and Murumägi, Astrid , et al. (2017) In Blood Advances 1(24). p.2257-2268
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... (More)
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. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Blood Advances
volume
1
issue
24
pages
2257 - 2268
publisher
American Society of Hematology
external identifiers
  • scopus:85052974761
ISSN
2473-9529
DOI
10.1182/bloodadvances.2017010215
language
Swedish
LU publication?
yes
id
e16687bd-9c32-478d-8279-7fa16498c85f
date added to LUP
2019-02-05 19:59:35
date last changed
2024-02-14 17:17:49
@article{e16687bd-9c32-478d-8279-7fa16498c85f,
  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.}},
  author       = {{Karvonen, Hanna and Chiron, David and Niininen, Wilhelmiina and Ek, Sara and Jerkeman, Mats and Moradi, Elaheh and Nykter, Matti and Heckman, Caroline A. and Kallioniemi, Olli and Murumägi, Astrid and Ungureanu, Daniela}},
  issn         = {{2473-9529}},
  language     = {{swe}},
  month        = {{11}},
  number       = {{24}},
  pages        = {{2257--2268}},
  publisher    = {{American Society of Hematology}},
  series       = {{Blood Advances}},
  title        = {{Crosstalk between ROR1 and BCR pathways defines novel treatment strategies in mantle cell lymphoma.}},
  url          = {{http://dx.doi.org/10.1182/bloodadvances.2017010215}},
  doi          = {{10.1182/bloodadvances.2017010215}},
  volume       = {{1}},
  year         = {{2017}},
}