Format

Send to

Choose Destination
Mol Cancer Ther. 2017 Nov;16(11):2473-2485. doi: 10.1158/1535-7163.MCT-16-0834. Epub 2017 Sep 1.

Inhibition of Discoidin Domain Receptor 1 Reduces Collagen-mediated Tumorigenicity in Pancreatic Ductal Adenocarcinoma.

Author information

1
Division of Surgical Oncology, Department of Surgery and Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, Texas.
2
School of Pharmacy, Jinan University, Guangzhou, China.
3
Department of Pathology, UT Southwestern Medical Center, Dallas, Texas.
4
Department of Pathology, UT MD Anderson Cancer Center, Houston, Texas.
5
Department of Surgical Oncology, UT MD Anderson Cancer Center, Houston, Texas.
6
Department of Clinical Science, UT Southwestern Medical Center, Dallas, Texas.
7
Division of Surgical Oncology, Department of Surgery and Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, Texas. Rolf.Brekken@utsouthwestern.edu.
8
Department of Pharmacology, UT Southwestern Medical Center, Dallas, Texas.

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.

PMID:
28864681
PMCID:
PMC5669827
DOI:
10.1158/1535-7163.MCT-16-0834
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center