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  • However there are still some issues that remain poorly

    2020-05-21

    However, there are still some issues that remain poorly understood. For instance, how TGF-β modulates DDR2 expression and whether Smads participate in the regulation. How does DDR2 regulate the expression of PTHrP via Runx2? Is there any other kinase downstream of DDR2 participating in PTHrP regulation, such as p38? These questions would be answered in our future studies.
    Materials and methods
    Conflict of interest
    Acknowledgments This work is supported by the National Natural Science Foundation of China (No. 81300716), the Specialized Research Fund for the Doctoral Program of Higher Education (No. 20120201120089) and the Scientific Research Fund of Shaanxi Provincial Department of Health (No. 2012D59).
    Squamous cell cancers (SCCs) of the lung develop from bronchial epithelial YM 155 as a result of squamous metaplasia and are typically found in smokers. The standard of care for this disease is a chemotherapy regimen of four to six cycles of platinum doublets in the first-line setting. Prognosis is often poor with objective response rates of 30% to 40% and a median survival of 12 months for patients with stage IIIb/IV disease. Clinical trials of targeted therapies in lung SCCs have not shown any patient benefit and in some cases led to greater toxicity. For instance, treatment with the vascular endothelial growth factor receptor inhibitor bevacizumab resulted in an increased risk of bleeding complications in SCC patients in phase II trials and is currently approved only in non-squamous non–small-cell lung carcinoma., Another example is the insulin-like growth factor-1 receptor inhibitor figitumumab that showed increased toxicity when combined with chemotherapy compared with chemotherapy alone, resulting in the closure of phase III clinical trials. The failure of these trials underscore the need for a comprehensive understanding of the biology of lung SCC, in particular how genetic aberrations manifest at the signaling level to promote tumorigenesis and dictate therapeutic response. The differential responses to targeted therapies between lung adenocarcinomas and SCCs in the clinical setting suggest that the biology and genetic landscape of these two diseases are unique. Indeed, recent lung SCC sequencing studies by Hammerman et al., demonstrate that the genomic aberrations in SCCs are distinct from adenocarcinomas. DDR2 AND LUNG SCCS In an exon sequencing study, Hammerman et al. identified the discoidin domain receptor 2 (DDR2) gene as a potential oncogenic target in lung SCC. The authors screened 290 tumors and cell lines and reported a 3.8% incidence of DDR2 point mutations in lung SCC samples. This frequency is similar to the incidence of EML4-ALK in lung adenocarcinomas. Additional DDR2 mutations at 4.4% frequency have since been identified in an independent cohort of lung SCC patients. It is likely that early targeted sequencing studies failed to identify any aberrations in the DDR2 gene because of small patient cohort size., A lower mutation frequency of 1.1% was reported in a large-scale next generation sequencing study in a cohort of 178 SCC patients performed by the TCGA Network, whereas no mutations were found in a screen of 166 SCC biopsies from Japanese patients. In the latter case, Sasaki et al proposed that their inability to detect any DDR2 mutations may have been related to ethnic differences in the sample populations. The DDR2 point mutations are not localized to hotspot regions and are distributed throughout the gene, including the extracellular ligand-binding discoidin domain and the cytoplasmic kinase domain. Interestingly, data emerging from lung adenocarcinoma sequencing studies have also identified DDR2 mutations at 2% to 5% frequency (http://www.cbioportal.org/). Again, these mutations are spread across the gene but were not found to be significantly enriched over the background mutational rate of the tumors analyzed. The biological role of DDR2 in lung adenocarcinoma remains to be investigated. DDR2 is a receptor tyrosine kinase, which also functions as an adhesion receptor that is activated by collagen, a major component of the extracellular matrix in the lung. Hammerman et al. showed that a subset of these DDR2 mutants is tumor promoting in cell lines in vitro. Depletion of mutant DDR2 using RNA interference in lung SCC cells demonstrated oncogene addiction. Importantly, this class of mutations is sensitive to inhibition by the FDA-approved tyrosine kinase inhibitor dasatinib in both in vitro assays and in subcutaneous xenograft models in vivo, making it clinically actionable and amenable to rapid advancement into lung SCC trials.,