The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access)
PANCREATIC RIBONUCLEASE FUNCTIONS AS AN EPIDERMAL GROWTH FACTOR RECEPTOR LIGAND INDEPENDENTLY OF ITS ENZYME ACTIVITY AND CONTRIBUTES TO CETUXIMAB RESISTANCE
Date of Graduation
Doctor of Philosophy (PhD)
Stephanie S. Watowich
Min Gyu Lee
Ribonuclease (RNase) with its catalytic enzyme activity to degrade RNAs has been shown as a diagnostic serum marker for pancreatic cancer and has also been suspected to have an unidentified cell surface receptor. Epidermal growth factor receptor (EGFR), a well-characterized receptor tyrosine kinase is an effective therapeutic target in multiple cancer types. However, clinical trials targeting EGFR have not demonstrated improved therapeutic efficacy in pancreatic cancer. Here, we show that both bovine pancreatic RNase A (bRNaseA) and human RNase 5 (hRNase5) act as EGFR ligands and directly activate EGFR to promote epithelial-mesenchymal transition. This ligand-like activity is independent of RNases’ enzymatic activity. In addition, Gln93 and Tyr94 of hRNase5, which are highly conserved between hRNase5 and EGF, are critical for efficient binding to EGFR. A statistically positive correlation between hRNase5 and activated EGFR expression in human pancreatic tissue microarrays further supports the pathological relevance of hRNase5. Strikingly, hRNase5 also enhances resistance to cetuximab therapy in pancreatic cancer. Thus, there may be an interplay between serum RNase and overexpressed EGFR in human cancers, especially in pancreatic cancer, that leads to aggressive cancer behaviors. Our findings uncover a potential opportunity for therapeutic intervention by rational combination therapy of hRNase5 inhibition and cetuximab.
EGFR, Ribonuclease, Pancreatic Cancer, Cetuximab