ABSTRACT
The extracellular matrix (ECM), a principal component of pancreatic ductal adenocarcinoma (PDA), is rich in fibrillar collagens that facilitate tumor cell survival and chemoresistance. Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase that specifically binds fibrillar collagens and has been implicated in promoting cell proliferation, migration, adhesion, ECM remodeling, and response to growth factors. We found that collagen-induced activation of DDR1 stimulated protumorigenic signaling through protein tyrosine kinase 2 (PYK2) and pseudopodium-enriched atypical kinase 1 (PEAK1) in pancreatic cancer cells. Pharmacologic inhibition of DDR1 with an ATP-competitive orally available small-molecule kinase inhibitor (7rh) abrogated collagen-induced DDR1 signaling in pancreatic tumor cells and consequently reduced colony formation and migration. Furthermore, the inhibition of DDR1 with 7rh showed striking efficacy in combination with chemotherapy in orthotopic xenografts and autochthonous pancreatic tumors where it significantly reduced DDR1 activation and downstream signaling, reduced primary tumor burden, and improved chemoresponse. These data demonstrate that targeting collagen signaling in conjunction with conventional cytotoxic chemotherapy has the potential to improve outcome for pancreatic cancer patients. Mol Cancer Ther; 16(11); 2473-85. ©2017 AACR.
Subject(s)
Adenocarcinoma/drug therapy , Carcinogenesis/drug effects , Carcinoma, Pancreatic Ductal/drug therapy , Discoidin Domain Receptor 1/genetics , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Animals , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/pathology , Cell Adhesion/drug effects , Cell Movement/drug effects , Cell Proliferation/drug effects , Collagen/metabolism , Discoidin Domain Receptor 1/antagonists & inhibitors , Focal Adhesion Kinase 1/genetics , Humans , Mice , Protein-Tyrosine Kinases/genetics , Signal Transduction/drug effects , Small Molecule Libraries/administration & dosage , Xenograft Model Antitumor AssaysABSTRACT
The function of transforming growth factor ß (TGFß) in the progression of pancreatic ductal adenocarcinoma (PDA) is complex and therapeutic targeting of this pathway is challenging. We showed that antibody-mediated inhibition of stromal Tgfßr2 prevented or reversed epithelial plasticity resulting in a potent reduction of metastasis in xenograft models of PDA.
ABSTRACT
Elevated levels of TGFß are a negative prognostic indicator for patients diagnosed with pancreatic cancer; as a result, the TGFß pathway is an attractive target for therapy. However, clinical application of pharmacologic inhibition of TGFß remains challenging because TGFß has tumor suppressor functions in many epithelial malignancies, including pancreatic cancer. In fact, direct neutralization of TGFß promotes tumor progression of genetic murine models of pancreatic cancer. Here, we report that neutralizing the activity of murine TGFß receptor 2 using a monoclonal antibody (2G8) has potent antimetastatic activity in orthotopic human tumor xenografts, syngeneic tumors, and a genetic model of pancreatic cancer. 2G8 reduced activated fibroblasts, collagen deposition, microvessel density, and vascular function. These stromal-specific changes resulted in tumor cell epithelial differentiation and a potent reduction in metastases. We conclude that TGFß signaling within stromal cells participates directly in tumor cell phenotype and pancreatic cancer progression. Thus, strategies that inhibit TGFß-dependent effector functions of stromal cells could be efficacious for the therapy of pancreatic tumors. Cancer Res; 74(18); 4996-5007. ©2014 AACR.
