Based on the clinical promise of counteracting drug resistance, especially in difficult-to-treat malignancies such as pancreatic cancer, we investigated the impact of 1,3,4-O-Bu3ManNAc on EGFR signaling to gain insight into the underlying molecular mechanisms by which this compound attenuated oncogenic signaling and to understand the unusual synergy between TKIs and increased cellular sialylation supported by this compound. This evidence concerns the gene EGFR and familial pancreatic carcinoma.