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EMBO Mol Med. 2018 Feb 9. pii: e7918. doi: 10.15252/emmm.201707918. [Epub ahead of print]

Inhibition of DDR1-BCR signalling by nilotinib as a new therapeutic strategy for metastatic colorectal cancer.

Author information

1
CRBM, CNRS, University Montpellier, Montpellier, France.
2
Novartis Institutes for Biomedical Research, Postfach, Basel, Switzerland.
3
Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
4
IRCM, INSERM, University Montpellier, Montpellier, France.
5
IGF, CNRS, INSERM, University Montpellier, Montpellier, France.
6
CRBM, CNRS, University Montpellier, Montpellier, France serge.roche@crbm.cnrs.fr audrey.sirvent@crbm.cnrs.fr.

Abstract

The clinical management of metastatic colorectal cancer (mCRC) faces major challenges. Here, we show that nilotinib, a clinically approved drug for chronic myeloid leukaemia, strongly inhibits human CRC cell invasion in vitro and reduces their metastatic potential in intrasplenic tumour mouse models. Nilotinib acts by inhibiting the kinase activity of DDR1, a receptor tyrosine kinase for collagens, which we identified as a RAS-independent inducer of CRC metastasis. Using quantitative phosphoproteomics, we identified BCR as a new DDR1 substrate and demonstrated that nilotinib prevents DDR1-mediated BCR phosphorylation on Tyr177, which is important for maintaining β-catenin transcriptional activity necessary for tumour cell invasion. DDR1 kinase inhibition also reduced the invasion of patient-derived metastatic and circulating CRC cell lines. Collectively, our results indicate that the targeting DDR1 kinase activity with nilotinib may be beneficial for patients with mCRC.

KEYWORDS:

collagen receptor; colorectal cancer; invasion; targeted therapy; tyrosine kinase

PMID:
29438985
DOI:
10.15252/emmm.201707918
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