Combined inhibition of DDR1 and Notch signaling is a therapeutic strategy for KRAS-driven lung adenocarcinoma

Ambrogio, Chiara; Gómez‐López, Gonzalo; Falcone, Mattia; Vidal, August; Nadal, Ernest; Crosetto, Nicola; Blasco, Rafael; Fernández-Marcos, Pablo J.; Sánchez-Céspedes, Montserrat; Ren, Xiaomei; Wang, Zhen; Ding, Ke; Hidalgo, Manuel; Serrano, Manuel; Villanueva, Alberto; Santamarı́a, David; Barbacid, Mariano

doi:10.1038/nm.4041

Cited by 157 publications

(153 citation statements)

References 62 publications

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“…A recent study has shown that DDR1 was an interesting biomarker in renal cancer and that it promoted the epithelial to mesenchymal transition in cancer cells [27] . DDR1 expression was also enhanced in the early phases of KRAS-driven lung adenocarcinoma and its inhibition in vivo protected mice in an experimental model of this disease [28] . However, the molecular mechanisms downstream DDR1 activation in cancer cells are mostly unknown.…”

Section: Cancermentioning

confidence: 99%

“…Recent investigations have reported the synthesis of specific DDR1 and/or DDR2 inhibitors tested in vitro and/ or in vivo [28,48,49] . Kim et al [48] created 2 specific inhibitors of DDRs, DDR1-IN-1, and DDR1-IN-2 derived, respectively, from nilotinib and imatinib.…”

Section: Ddr1 As Target Of Therapymentioning

confidence: 99%

“…In addition, this compound inhibited DDR1 signaling in cells derived from a non-small cell lung carcinoma, thereby reducing their invasiveness. Finally, this compound has been successfully used in vitro and in vivo to inhibit DDR1 in a murine model of KRAS-driven lung adenocarcinoma [28] .…”

Section: Ddr1 As Target Of Therapymentioning

confidence: 99%

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The Role of Discoidin Domain Receptor 1 in Inflammation, Fibrosis and Renal Disease

Dorison

Dussaule²,

Chatziantoniou³

2017

Nephron

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Discoidin domain receptors (DDRs) are a family of 2 non-integrin collagen receptors, DDR1 and DDR2, which display a tyrosine kinase activity. They are mainly expressed during embryonic development and their role during adulthood is very limited. DDR1 has been widely studied in several types of cancers, in atherosclerosis and fibrosis, but also in chronic kidney disease (CKD). This review focuses on the role of DDR1 in chronic nephropathies and on the effect of its deletion in the pathological processes involved in renal disease progression. DDR1 was shown to be de novo expressed in several models of experimental CKD. Its genetic or pharmaco-genetic inhibition led to the preservation of renal structure and function, and to decreased inflammatory influx and fibrosis. Furthermore, delayed pharmaco-genetic inhibition of DDR1 led to significant protection in models of renal disease. These results demonstrate the involvement of DDR1 in inflammatory and fibrotic processes occurring during CKD and the beneficial effect of its inhibition. Thus, DDR1 could be an interesting therapeutic target to treat renal pathologies.

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Section: Cancermentioning

confidence: 99%

Section: Ddr1 As Target Of Therapymentioning

confidence: 99%

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The Role of Discoidin Domain Receptor 1 in Inflammation, Fibrosis and Renal Disease

Dorison

Dussaule²,

Chatziantoniou³

2017

Nephron

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“…In K-Ras-mutant lung cancers, Ambrogio et al (43) showed that combining 7rh to inhibit DDR1 with a Notch inhibitor was effective. In addition Ali-Rahmani et al (44) have shown inhibiting DDR1 with 7rh in combination with an immunotoxin caused shrinkage of tumor xenografts.…”

Section: Discussionmentioning

confidence: 99%

Up-regulation of N-cadherin by Collagen I-activated Discoidin Domain Receptor 1 in Pancreatic Cancer Requires the Adaptor Molecule Shc1

Huang¹,

Svoboda²,

Lazenby³

et al. 2016

Journal of Biological Chemistry

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Pancreatic ductal adenocarcinomas are highly malignant cancers characterized by extensive invasion into surrounding tissues, metastasis to distant organs, and a limited response to therapy. A main feature of pancreatic ductal adenocarcinomas is desmoplasia, which leads to extensive deposition of collagen I. We have demonstrated that collagen I can induce epithelialmesenchymal transition (EMT) in pancreatic cancer cells. A hallmark of EMT is an increase in the expression of the mesenchymal cadherin N-cadherin. Previously we showed up-regulation of N-cadherin promotes tumor cell invasion and that collagen I-induced EMT is mediated by two collagen receptors, ␣2␤1-integrin and discoidin domain receptor 1 (DDR1). DDR1 is a receptor-tyrosine kinase widely expressed during embryonic development and in many adult tissues and is also highly expressed in many different cancers. In the signaling pathway initiated by collagen, we have shown proline-rich tyrosine kinase 2 (Pyk2) is downstream of DDR1. In this study we found isoform b of DDR1 is responsible for collagen I-induced up-regulation of N-cadherin and tyrosine 513 of DDR1b is necessary. Knocking down Shc1, which binds to tyrosine 513 of DDR1b via its PTB (phosphotyrosine binding) domain, eliminates the upregulation of N-cadherin. The signaling does not require a functional SH2 domain or the tyrosine residues commonly phosphorylated in Shc1 but is mediated by the interaction between a short segment of the central domain of Shc1 and the proline-rich region of Pyk2. Taken together, these data illustrate DDR1b, but not DDR1a, mediates collagen I-induced N-cadherin up-regulation, and Shc1 is involved in this process by coupling to both DDR1 and Pyk2.Pancreatic cancer is currently the fourth leading cause of cancer-related mortality in the United States with a 5-year survival rate of ϳ6% (American Cancer Society, 2014). This unfortunate outcome is mainly due to the aggressive behavior of this cancer and the lack of symptoms early in the disease. One of the major features of pancreatic cancer is that during the early stages an extensive stromal reaction occurs called desmoplasia. A dense stroma forms, which consists of myofibroblasts (pancreatic stellate cells), abundant extracellular matrix, and different types of inflammatory cells including macrophages, mast cells, lymphocytes, and plasma cells (1, 2). The extracellular matrix components include collagens, fibronectin, hyaluronic acid, and proteoglycans, whereas the major part is type I collagen (3, 4).The atypical stroma plays many roles in pancreatic cancer. It changes the normal architecture of pancreatic tissue and induces an abnormal configuration of blood and lymphatic vessels resulting in a hypovascular and hypoxic microenvironment. It also presents a barrier to drug delivery and promotes tumor immunologic tolerance (2, 4). Previously, our laboratory showed that collagen I can induce epithelial-mesenchymal transition (EMT) 2 -like changes in pancreatic cancer mediated by two collagen receptors, ␣2␤1-integrin and ...

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“…DDR1 can induce pro- (5,44,69,71,72) and anti-(73-75) proliferative effects depending on the cell type. It was previously demonstrated that in KRAS-driven lung adenocarcinoma, DDR1 and Notch co-inhibition suppressed the activation of critical tumor survival-promoting signaling pathways (76). High DDR1 expression may also exhibit a positive effect in the proliferation and/or survival of breast cancer cells (46,77).…”

Section: Effects Of Ddr1 On the Apoptosis Or Survival Of Breast Cancementioning

confidence: 99%

Discoidin domain receptor 1: New star in cancer-targeted therapy and its complex role in breast carcinoma (Review)

2018

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Abstract. Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase activated by various types of collagens that performs a critical role in cell attachment, migration, survival and proliferation. The functions of DDR1 in various types of tumor have been studied extensively. However, in breast carcinoma, the roles of collagen-evoked DDR1 remain ill defined. Although a number of studies have reported that DDR1 promotes apoptosis and inhibits migration in breast carcinoma, it has also been reported to be associated with tumor cell survival, chemoresistance to genotoxic drugs and the facilitation of invasion. The present review summarizes current progress and the complex effects of DDR1 in the field of breast carcinoma, and presents DDR1 as a promising therapeutic target.

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Combined inhibition of DDR1 and Notch signaling is a therapeutic strategy for KRAS-driven lung adenocarcinoma

Cited by 157 publications

References 62 publications

The Role of Discoidin Domain Receptor 1 in Inflammation, Fibrosis and Renal Disease

The Role of Discoidin Domain Receptor 1 in Inflammation, Fibrosis and Renal Disease

Up-regulation of N-cadherin by Collagen I-activated Discoidin Domain Receptor 1 in Pancreatic Cancer Requires the Adaptor Molecule Shc1

Discoidin domain receptor 1: New star in cancer-targeted therapy and its complex role in breast carcinoma (Review)

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