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

The clinical management of metastatic colorectal cancer (mCRC) faces major challenges. For instance, patients harbouring oncogenic mutations in RAS signalling do not respond to anti-EGFR targeted treatment. Therefore, RAS-independent therapies are needed. Interestingly nilotinib, a clinically approved drug for chronic myeloid leukaemia, 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 -catenin transcriptional activity necessary for tumour cell invasion. DDR1 kinase inhibition also reduced the invasion of patient-derived metastatic and circulating CRC cell lines.