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    • br Acknowledgments I thank Erhard

    2020-08-03


    Acknowledgments I thank Erhard Hohenester for critical reading of this manuscript and for providing Fig. 2.2. I acknowledge funding from the Medical Research Council UK (Grant G0701121) and the Biotechnology and Biological Sciences Research Council UK (Grant BB/I011226/1).
    Introduction Imatinib (Gleevec®, STI571), is an inhibitor of the tyrosine kinase activity of BCR-ABL and is the first-line therapy for chronic myelogenous leukemia. Although most patients respond very well to imatinib therapy, resistance can develop in a subpopulation of advanced stage chronic myelogenous leukemia patients. Resistance is frequently due to the emergence of clones expressing mutant forms of BCR-ABL which are not sensitive to imatinib. Two second-generation agents, nilotinib (Tasigna®, AMN107) and dasatinib (Sprycell®, BMS-354825), which maintain activity against many imatinib-resistant, mutant forms of BCR-ABL, have been introduced to treat imatinib-intolerant and -resistant chronic myelogenous leukemia (Weisberg et al., 2005). Several other compounds are also being developed for imatinib-resistant chronic myelogenous leukemia (Weisberg et al., 2007). Whereas imatinib and nilotinib are relatively selective tyrosine kinase inhibitors, dasatinib is a multi-targeted kinase inhibitor, which in addition to inhibiting BCR-ABL, potently inhibits many additional kinases, including those of the SRC kinase family (Shah et al., 2004, Weisberg et al., 2007). A recent chemical proteomics study of Abelson kinase inhibitors has identified Discoidin Domain Receptor1 as an additional target of imatinib in K562 leukemia atp enzyme mg (Bantscheff et al., 2007). More recently, by generating drug–protein interaction profiles it has also been demonstrated that DDR1 can also bind nilotinib and dasatinib, which, in turn, can inhibit DDR1 activity (Rix et al., 2007). DDR1 is one of two, non-integrin tyrosine kinase receptors activated by collagen. Although DDR1 has five isoforms (1a, 1b, 1c, 1d, 1e) generated by alternative splicing, only DDR1a and 1b have active kinase domains, whereas DDR2, encoded by a distinct gene, has one isoform (Vogel et al., 2006). Collagen binding requires dimerization of the extra-cellular domains and results in receptor auto-phosphorylation. DDR1 is widely expressed during embryonic development and in adult tissues, with expression in the epithelium of a variety of tissues, particularly in skin, kidney, lung, gut, and brain (Vogel et al., 2006). DDR2 is expressed primarily in mesenchymal cells including fibroblasts, myofibroblasts, smooth muscle, and skeletal muscle in several tissues including skin, kidney, lung, heart and connective tissues. DDRs have been proposed to play important roles in a number of diseases. High levels of DDR1 and 2 expression have been observed in several tumours of breast, ovarian, lung and brain origin (Barker et al., 1995, Nemoto et al., 1997, Weiner et al., 2000). DDR1 receptor over-expression has also been implicated in cell survival and invasiveness in hepatocellular carcinoma, pituitary adenoma and prostate cancer (Park et al., 2007, Yoshida and Teramoto, 2007, Shimada et al., 2008). DDR1, particularly the 1b isoform has also been implicated in idiopathic pulmonary fibrosis. Selective induction of DDR1b in CD14+ cells from idiopathic pulmonary fibrosis patients has been shown to lead to production of several inflammatory chemokines upon collagen induction (Matsuyama et al., 2005a). Suppression of DDR1 in the bleomycin model in vivo using siRNA or in DDR1-deficient mice has lead to the attenuation of fibrosis and inflammation (Avivi-Green et al., 2006, Matsuyama et al., 2006). In sarcoidosis, DDR1 expression levels in CD14+ bronchoalveolar lavage cells appear to correlate with deterioration of the disease (Matsuyama et al., 2005b). Both DDR1 and 2 are expressed in atherosclerotic and lymphangioleiomyomatotic lesions and appear to participate in the regulation of collagen turnover by smooth muscle cells (Ferri et al., 2004). DDR1 null mice are protected in a mouse model of kidney fibrosis and implicate the receptor in both inflammatory and fibrotic components of the disease (Flamant et al., 2006). The over-expression of DDR2 has been observed in the cartilage in patients with osteoarthritis (Xu et al., 2007) and in the context of liver fibrosis it has been shown that the induction of fibrosis in an animal model resulted in up-regulation of DDR2 in stellate cells (Olaso et al., 2001).