Volume 7 Supplement 2

São Paulo Advanced School of Comparative Oncology: Abstracts

Open Access

ROR1 is a pseudokinase that is crucial for MET-driven tumorigenesis

  • Luca Lazzari1, 3Email author,
  • Alessandra Gentile1,
  • Silvia Benvenuti1,
  • Livio Trusolino2, 3 and
  • Paolo M Comoglio1, 3
BMC Proceedings20137(Suppl 2):P43

DOI: 10.1186/1753-6561-7-S2-P43

Published: 4 April 2013

Background

Aberrant deregulation of some Receptor Tyrosine Kinases (RTKs) signalling underlies diverse facets of tumor pathobiology providing an attractive target for cancer therapy. Searching for novel cancer-associated RTKs is an important issue to discover new therapeutic opportunities. For this reason, we investigated the contribution of Receptor tyrosine kinase-like Orphan Receptor 1 (ROR1) to human cancer.

Patients and methods

The level of ROR1 protein expression, phosphorylation and cellular growth response to RNAi-mediated ROR1 knockdown was evaluated by an integrated screening in a panel of 43 cancer cell lines. ROR1 auto-kinase activity and transphosphorylation were determined by biochemical assays. Functional consequences of ROR1 silencing were evaluated by several in vitro and in vivo biological assays.

Results

We demonstrated that although ROR1 is expressed in approximately 75% of the screened cancer cell lines, only gastric carcinoma cells (HS746T) and non-small cell lung carcinoma cells (NCI-H1993) exhibit high levels of ROR1 tyrosine phosphorylation and experience growth inhibition upon ROR1 suppression. Biochemical assays revealed that ROR1 is a pseudokinase lacking autocatalytic activity. Intriguingly, the two phospho-ROR1 positive cell lines both exhibited amplification and constitutive activation of the MET oncogene. ROR1 phosphorylation was abrogated by MET inhibition, indicating MET dependent transphosphorylation of ROR1. Silencing of ROR1 in HS746T and NCI-H1993 cells impaired cellular proliferation, growth and migration in vitro and induced a dramatic inhibition of tumorigenesis in vivo.

Conclusions

Our data show that ROR1 is a pseudokinase functionally transphosphorylated by MET RTK, suggesting a critical role for ROR1 in malignant phenotypes sustained by the MET oncogene.

Financial support

AIRC special program Molecular Clinical Oncology “5x1000” and AIRC grants.

Authors’ Affiliations

(1)
Exploratory Research Laboratory, Institute for Cancer Research and Treatment (IRCC)
(2)
Molecular Pharmacology Laboratory, Institute for Cancer Research and Treatment (IRCC)
(3)
Department of Oncological Sciences, University of Turin Medical School

Copyright

© Lazzari et al; licensee BioMed Central Ltd. 2013

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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