The central coordinator of the genotoxic/DNA damage stress response is tumor suppressor p53, which regulates the expression of genes involved in cell cycle arrest and apoptosis. We previously identified DDR1 kinase as a direct target gene of p53. We found that, unlike other typical p53 target genes, DDR1 kinase promotes cell survival by offsetting p53-mediated apoptosis in cancer cells containing WT p53. DDR1 was originally identified in a screen for tyrosine kinase proteins expressed in human malignancies and also found as one of several major activated tyrosine kinases in a variety of human cancers. From recent functional cancer genomics efforts (Norvatis/Broad Consortium), DDR1 is amplified, and mutated in many types human malignancies, including epithelial cancers and lymphomas. However, the specific molecular mechanism(s) by which this receptor may contribute to oncogenesis remains incompletely understood. Our preliminary data show that several DDR1 mutations in human cancer cell lines appear to promote constitutively activation of DDR1 and exert resistance to broad kinase inhibitors such as dastinib and iressa. Our studies clearly demonstrate the essential role of the DDR1 pathway in maintaining cancer cell survival, proliferation and migration/invasion. Subsequently, we have identified EMT regulators as a downstream pathway of DDR1. Using integrated biochemical, therapeutic and genetic approaches in vitro and in vivo, the overall goal of this application is to elucidate the specific molecular mechanism by which DDR1 alterations contribute to tumorigenesis and pro-survival in response to genotoxic stress. We hypothesize that while p53-dependent up-regulation of DDR1 plays a protective role against genotoxic stress/DNA damage, DDR1 mutations are important oncogenic events in a subset of cancer cells that contribute to cell survival and play a role in chemo-resistance in cancer cells. Further understanding of this unexplored pathway underlying DDR1-mediated prosurvival/protective response in vitro and in vivo is expected to eventually translate into therapeutic benefits for the treatment of tumors. To test the above hypotheses, we propose the following three specific aims: firstly to investigate the functional significance and oncogenic potential of constitutive DDR1 receptor kinase activation resulting from genomic alterations in vitro and in vivo, and secondly to examine whether DDR1-deficiency results in the suppression of tumorigenesis and protective response to genotoxic stress in vivo;
this aim will investigate how DDR1- deficiency contributes to mammary tumor progression and to genotoxic stress response in a genetic mouse tumor model.
Recent studies have reported altered expression of DDR1 in human tumors, including lung, esophagus, breast, ovary, and brain cancer, suggesting a potential role for DDR1 in tumor development although the precise mechanism by which this receptor may contribute to oncogenesis is still unknown. Understanding of this unexplored cell survival pathway underlying DDR1 oncogenic and survival pathway is expected to eventually translate into therapeutic benefit in the treatment of tumors.
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