Pancreatic ribonuclease (RNase) is a secreted enzyme critical for host defense. We discover an intrinsic RNase function, serving as a ligand for epidermal growth factor receptor (EGFR), a member of receptor tyrosine kinase (RTK), in pancreatic ductal adenocarcinoma (PDAC). The closely related bovine RNase A and human RNase 5 (angiogenin ANG) can trigger oncogenic transformation independently of their catalytic activities via direct association with EGFR. Notably, high plasma ANG level in PDAC patients is positively associated with response to EGFR inhibitor erlotinib treatment. These results identify a role of ANG as a serum biomarker that may be used to stratify patients for EGFR-targeted therapies, and offer insights into the ligand-receptor relationship between RNase and RTK families. Display omitted •ANG acts as an EGFR ligand in an RNase catalytic-independent manner•Depletion of ANG highlights an oncogenic role of the ANG-EGFR axis in PDAC•High ANG level serves as a serum biomarker to predict erlotinib response•New insight into ligand-receptor relationship between RTK and RNase families Wang et al. identify angiogenin (ANG) as a ligand for epidermal growth factor receptor (EGFR). ANG-mediated EGFR activation can trigger oncogenic transformation, and high ANG in the plasma of pancreatic adenocarcinoma patients positively correlates with response to the EGFR inhibitor erlotinib.