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  • Our knowledge of DDR induced


    Our knowledge of DDR-induced signaling pathways is still fragmentary. In particular, we do not know which signaling effectors interact with the phosphorylated receptors and how different effectors are linked to the control of specific cellular functions. The DDRs are at the interface between RTKs and ECM receptors and DDR signaling intersects with signaling pathways triggered by other receptor systems, but again, we have little understanding about the pathways involved and how cells use this receptor cross talk to fine-tune cellular outcome. Since collagen-independent functions have emerged for DDR1, it is likely that other receptors, perhaps other RTKs, can induce DDR activation, but collagen-independent DDR functions are as yet poorly characterized. Collagen-induced DDR activation is required for normal embryo development and tissue homeostasis, but we have little understanding about how DDRs control matrix remodeling. It is likely that their roles go beyond simply controlling MMP expression and that their physical interaction with collagen may be required to control not only the size or diameter of collagen fibers but also their orientation and alignment (Flynn et al., 2010, Zhang et al., 2013). New roles for DDRs in disease progression have emerged in recent studies, but the validation of the DDRs as drug targets is still incomplete. In particular, it is not clear for which diseases the DDR kinase activity is essential. Common drugs in targeted RTK therapies use small molecule kinase inhibitors, which would be useless in diseases that are not DDR kinase dependent. Furthermore, since all RTK kinases (and nonreceptor kinases) share similar structures, it is very difficult to obtain drugs with high specificity and selectivity. Successful anti-RTK therapies based on monoclonal PX-478 2HCl against RTK ectodomains are in clinical use (e.g., herceptin/trastuzumab for HER2 positive metastatic breast cancer). Future anti-DDR therapies may involve the generation of blocking antibodies, such as were developed for DDR1 (Carafoli et al., 2012). However, it remains to be seen whether blocking DDR1 antibodies are effective in halting or reversing disease progression in animal models. Another avenue may be the development of therapies that block DDR expression, such as targeted delivery of RNAi-based therapeutics.
    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 cells (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).