Disrupting Collagen-Mediated Pro-Survival Pathways in Pancreatic Cancer
Abstract
This application proposes to inhibit the Discoidin Domain Receptor 1 (DDR1) both with a single agent and in conjunction with drugs targeting RAS-MEK-ERK as a new possible treatment for Pancreatic Ductal Adenocarcinoma (PDAC). We hypothesize that DDR1 mediate the crosstalk between mutant Kras addicted PDAC cells with collagen, and thereby activate signaling pathways that promote tumor cell survival and malignancy (MEK resistance). Thus, disrupting DDR1 function by pharmacological or genetic means may attenuate PDAC pro-survival/fibrotic pathways and enhance therapeutic efficacy drugs targeting Kras-driven (MEK) signaling networks. In our studies, we demonstrated that silencing of DDR1 enhances the sensitivity of PDAC cells to Trametinib, a MEK inhibitor. We characterized a novel selective DDR1 kinase inhibitor for its ability to dampen DDR1 activation by collagen. This inhibitor in combination with Trametinib reduced the proliferation of two PDAC human cell lines only in the presence of collagen, suggesting that DDR1 activation may synergize the MAPK pathway to confer resistance to MEK inhibition. These results are consistent with data indicating that DDR1 is critical for the development and progression of PDAC.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2020
- Accession Number
- AD1109486
Entities
People
- Rafael Fridman
Organizations
- Wayne State University