Inhibition of discoidin domain receptor 1 reduces collagen-mediated tumorigenicity in pancreatic ductal adenocarcinoma

Kristina Y. Aguilera, Huocong Huang, Wenting Du, Moriah M. Hagopian, Zhen Wang, Stefan Hinz, Tae Hyun Hwang, Huamin Wang, Jason B. Fleming, Diego H. Castrillon, Xiaomei Ren, Ke Ding, Rolf A. Brekken

Research output: Contribution to journalArticle

24 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2473-2485
Number of pages13
JournalMolecular Cancer Therapeutics
Volume16
Issue number11
DOIs
StatePublished - Nov 1 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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