DDR1 inhibition as a new therapeutic strategy for colorectal cancer

Abstract

The clinical management of metastatic colorectal cancer (mCRC) is still a major challenge. Recently, we discovered that nilotinib, an approved treatment for chronic myeloid leukaemia, inhibits invasive and metastatic properties of CRC cells by targeting the kinase activity of receptor for collagens DDR1 (Discoïdin Domain Receptor tyrosine kinase 1), suggesting that nilotinib could be an effective strategy to treat mCRC.

Keywords: DDR1 tyrosine kinase receptor; collagen; colorectal cancer; invasion; metastasis; nilotinib; targeted therapy.

Figure 1.

Inhibition of DDR1-BCR signaling by nilotinib. Collagens from the extracellular matrix (ECM) microenvironment of colorectal cancer (CRC) cells induce the kinase activity of DDR1 (Discoïdin Domain Receptor tyrosine kinase 1), which phosphorylates its substrate BCR (Breakpoint Cluster Region) on the tyrosine 177 (Y177), subsequently disrupting BCR/β-catenin interaction. This signaling cascade results in an increased β-catenin/TCF (T-Cell Factor) nuclear activity leading to the expression of critical target genes (including MYC, JUN, FOSL1, CD44, LGR5, CCND1) necessary for cell invasion and metastatic development (left panel). Inhibition of DDR1 kinase activity with nilotinib decreases CRC cell invasion and metastasis by reducing this β-catenin pathway (right panel).