Recent Advances in the Role of Discoidin Domain Receptor Tyrosine Kinase 1 and Discoidin Domain Receptor Tyrosine Kinase 2 in Breast and Ovarian Cancer

Abstract

Discoidin domain receptor tyrosine kinases (DDRs) are a class of receptor tyrosine kinases (RTKs), and their dysregulation is associated with multiple diseases (including cancer, chronic inflammatory conditions, and fibrosis). The DDR family members (DDR1a-e and DDR2) are widely expressed, with predominant expression of DDR1 in epithelial cells and DDR2 in mesenchymal cells. Structurally, DDRs consist of three regions (an extracellular ligand binding domain, a transmembrane domain, and an intracellular region containing a kinase domain), with their kinase activity induced by receptor-specific ligand binding. Collagen binding to DDRs stimulates DDR phosphorylation activating kinase activity, signaling to MAPK, integrin, TGF-β, insulin receptor, and Notch signaling pathways. Abnormal DDR expression is detected in a range of solid tumors (including breast, ovarian, cervical liver, gastric, colorectal, lung, and brain). During tumorigenesis, abnormal activation of DDRs leads to invasion and metastasis, via dysregulation of cell adhesion, migration, proliferation, secretion of cytokines, and extracellular matrix remodeling. Differential expression or mutation of DDRs correlates with pathological classification, clinical characteristics, treatment response, and prognosis. Here, we discuss the discovery, structural characteristics, organizational distribution, and DDR-dependent signaling. Importantly, we highlight the key role of DDRs in the development and progression of breast and ovarian cancer.

Proteome and phosphoproteome signatures of recurrence for HPV+ head and neck squamous cell carcinoma

“…PDGFRB plays a critical role in CAF proliferation while DDR1 is a collagen receptor 47 . Together these two RTKs may play an important role in regulating fibrosis 47 , 48 . The macrophage-stimulating protein receptor MST1R (or RON), which regulates the migration and activation of macrophages and activates wound-healing responses 49 , may play the dual role of promoting TAM and MDSC recruitment and fibrosis.…”

E-Cadherin-Deficient Cells Are Sensitive to the Multikinase Inhibitor Dasatinib

“…Functionally, DDR2 activity and downstream signalling has been associated with cell proliferation, survival, adhesion, spreading and differentiation [ 60 ]. Activated DDR2 has been shown to signal through a number of pathways including ERK, MAPK, PI3K and possibly FAK [ 61 , 62 ] Induction of EMT in a variety of model systems has been demonstrated to correlate with a switch from the expression of the more epithelial DDR1 to the more mesenchymal DDR2 [ 60 , 63 ]. In a human mammary epithelial cell line, the expression of EMT inducers, such as Snail, Slug and TGF-ß induced an “EMT core signature” which included an upregulation of DDR2 expression concomitant to a down regulation of DDR1 [ 64 ].…”

Identification of Synergistic Drug Combinations to Target KRAS-Driven Chemoradioresistant Cancers Utilizing Tumoroid Models of Colorectal Adenocarcinoma and Recurrent Glioblastoma

“…This study points to the significance of complementary cascades and pathway shunts that play a role in augmenting treatment resistance, highlighting the significance of combination therapies in recurrent tumors. DDR1 is a receptor for ECM proteins, collagens, which became overexpressed as tumors progress, and plays a central role in angiogenesis, tumor cell migration, and invasion ( 135 – 137 ). Stromal expression of DDR1 has also been shown to promote the growth of tumors harboring WNT-activated phenotype ( 138 ), and collagens have been widely documented as prognostic markers in colon cancer progression to metastasis ( 139 – 146 ).…”