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The extracellular matrix limits the efficacy of chemotherapy in pancreatic ductal adenocarcinoma (PDA) in part by active cell signaling. Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase that binds fibrillar collagens and is expressed by PDA tumor cells. The image shows phosphorylated DDR1 staining in human PDA highlighting active collagen signaling in PDA tumor cells. Aguilera and colleagues demonstrate that pharmacologic inhibition of DDR1 with the small molecule 7rh substantially improves the efficacy of standard chemotherapy in robust preclinical models of PDA in the absence of additional normal tissue toxicity.