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

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 DDR1mediated BCR phosphorylation on Tyr177, which is important for maintaining b-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.
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https://hal.archives-ouvertes.fr/hal-01872978
Contributor : Yvan Boublik <>
Submitted on : Tuesday, January 12, 2021 - 3:33:56 PM
Last modification on : Thursday, March 4, 2021 - 4:18:02 PM

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Maya Jeitany, Cédric Leroy, Priscillia Tosti, Marie Lafitte, Jordy Le Guet, et al.. Inhibition of DDR1-BCR signalling by nilotinib as a new therapeutic strategy for metastatic colorectal cancer. EMBO Molecular Medicine, Wiley Open Access, 2018, 10 (4), pp.e7918. ⟨10.15252/emmm.201707918⟩. ⟨hal-01872978⟩

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