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  • There have been two reports of tumor shrinkage

    2020-03-31

    There have been two reports of tumor shrinkage in response to dasatinib treatment in lung SCC patients harboring the DDR2 kinase domain S768R mutation., In the first case described by Hammerman et al. a combination of erlotinib (an epithelial growth factor receptor inhibitor) and dasatinib was administered to a patient whose disease had progressed despite carboplatin and paclitaxel therapy. Within 2 months of treatment, this patient showed a partial response and tumor shrinkage. She remained on the combination regimen for 14 months before discontinuation because of toxicity. In the second case study reported by Pitini et al., the patient had a rare instance of a BCR-ABL positive chronic myelogenous leukemia and a DDR2 S768R mutation in a lung SCC lesion. Dasatinib therapy resolved both the chronic myelogenous leukemia and the lung tumor after 10 weeks and the patient remained clinically well 8 months into the treatment. These case studies provide an indication that a subset of DDR2 mutations is oncogenic in this disease. Ongoing phase II trials assessing the efficacy of dasatinib in lung SCC (NCT01491633 and NCT01514864) are undertaking correlation analysis of DDR2 mutational status with response to therapy to validate the clinical relevance of these experimental findings.
    DDR2 SIGNALING NETWORKS DDR2 has been implicated in a number of cancer types and has been shown to play a role in driving proliferation and Reversine sale (see Borza and Pozzi and Valiathan et al. for recent excellent reviews on this topic). There is limited information available on the signaling pathways activated by DDR2 on collagen engagement. Work done by several research groups have shown that DDR2 activates important signaling components including SHC, SRC, JAK, ERK1/2, and PI3K (summarized in Fig. 1). In addition, Hammerman et al. used phosphorylation of STAT5 as a biological readout for DDR2 activity, although this signaling protein is unlikely to be a bona fide downstream substrate of the DDR2 pathway but rather the result of a survival signaling cascade in the IL-3 dependent Ba/F3 murine cell line. DDR2 also exhibits crosstalk with other cell surface receptors such as the integrins and RTKs resulting in diversification of downstream signal transduction networks.22, 23, 24, 25 Our laboratory has recently performed a global phosphoproteomic screen of DDR2 signaling activated by collagen I and identified 45 signaling effectors downstream of this receptor. In addition to the previously identified signaling nodes ERK1 and PI3K, these effectors also include novel protein substrates such as Lyn, SHP-2, SHIP-2, and PLCL2 (Fig. 1). We further show that these signaling events are independent of integrin activation by collagen and are specific to the DDR2 pathway. Similar to previous reports of signal transduction pathway adaptation in the epithelial growth factor receptor mutants often found in lung adenocarcinoma,, the identification of DDR2-specific signaling nodes will facilitate future studies on network reprogramming events that occur on acquisition of DDR2 mutations in cancer cells.
    IS DDR2 AN ONCOGENE OR A TUMOR SUPPRESSOR? There is some controversy regarding the role of DDR2 in cancer. Although Hammerman et al. showed that a subset of the DDR2 Reversine sale mutants, including the extracellular discoidin domain variant L63V and kinase domain variant I638F, are oncogenic, these assays were performed in the absence of its physiological ligand collagen. Furthermore, the activation and phosphorylation status of the receptor in these mutants were not established in this study. Fibrillar collagen inhibits cancer cell growth and one mechanism by which this process occurs is through a DDR2-dependent cell cycle arrest in melanoma and fibrosarcoma cells.29, 30, 31 It is plausible that DDR2 functions in a context-dependent manner and in the presence of its natural ligand collagen may act as a tumor suppressor rather than an oncogene. In support of this notion, mRNA levels of DDR2 are diminished in lung cancer tumors compared with matched normal lung tissue, suggesting a potential tumor suppressor role., This context dependence is reminiscent of the β1 integrin adhesion receptor that promotes tumor formation in transgenic mouse models of breast cancer but exhibits tumor suppressor-like properties in the TRAMP prostate adenocarcinoma model.,