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

Autor: 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
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Zdroj: EMBO Molecular Medicine, Vol 10, Iss 4, Pp 1-16 (2018)
Druh dokumentu: article
ISSN: 1757-4676
1757-4684
DOI: 10.15252/emmm.201707918
Popis: 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.
Databáze: Directory of Open Access Journals
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