Open AccessInhibition of DDR 1‐ BCR signalling by nilotinib as a new therapeutic strategy for metastatic colorectal cancer
Author(s) -
Jeitany Maya,
Leroy Cédric,
Tosti Priscillia,
Lafitte Marie,
Le Guet Jordy,
Simon Valérie,
Bonenfant Debora,
Robert Bruno,
Grillet Fanny,
Mollevi Caroline,
El Messaoudi Safia,
Otandault Amaëlle,
CanterelThouen Lucile,
Busson Muriel,
Thierry Alain R,
Martineau Pierre,
Pannequin Julie,
Roche Serge,
Sirvent Audrey
Publication year - 2018
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201707918
Subject(s) - nilotinib , cancer research , colorectal cancer , tyrosine kinase , ddr1 , metastasis , kinase , imatinib , medicine , receptor tyrosine kinase , cancer , biology , receptor , myeloid leukemia , microbiology and biotechnology
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 DDR 1, 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 DDR 1 substrate and demonstrated that nilotinib prevents DDR 1‐mediated BCR phosphorylation on Tyr177, which is important for maintaining β‐catenin transcriptional activity necessary for tumour cell invasion. DDR 1 kinase inhibition also reduced the invasion of patient‐derived metastatic and circulating CRC cell lines. Collectively, our results indicate that the targeting DDR 1 kinase activity with nilotinib may be beneficial for patients with mCRC .