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

Authors :
Maya Jeitany
Cédric Leroy
Priscillia Tosti
Marie Lafitte
Jordy Le Guet
Valérie Simon
Debora Bonenfant
Bruno Robert
Fanny Grillet
Caroline Mollevi
Safia El Messaoudi
Amaëlle Otandault
Lucile Canterel‐Thouennon
Muriel Busson
Alain R Thierry
Pierre Martineau
Julie Pannequin
Serge Roche
Audrey Sirvent
Source :
EMBO Molecular Medicine, Vol 10, Iss 4, Pp n/a-n/a (2018)
Publication Year :
2018
Publisher :
Springer Nature, 2018.

Abstract

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.

Details

Language :
English
ISSN :
17574684 and 17574676
Volume :
10
Issue :
4
Database :
Directory of Open Access Journals
Journal :
EMBO Molecular Medicine
Publication Type :
Academic Journal
Accession number :
edsdoj.79f020dc047450c9db38f20c405e854
Document Type :
article
Full Text :
https://doi.org/10.15252/emmm.201707918