Biomarker predicts response to pancreatic cancer therapy

MD Anderson researchers have discovered that a protein called angiogenin (ANG) serves as a potential biomarker useful for stratifying pancreatic ductal adenocarcinoma cancer (PDAC) patients for epidermal growth factor rector (EGFR)-targeted therapies.

Their research uncovered an intrinsic pancreatic ribonuclease (RNase) function that serves as a ligand for EGFR, a member of the receptor tyrosine kinase (TKR) family in PDAC. RNase is a secreted enzyme critical for host defense.

“This newly discovered EGFR ligand ANG serves as a serum biomarker to predict response to erlotinib, an EGFR tyrosine kinase inhibitor in pancreatic ductal adenocarcinoma,” said Mien-Chie Hung, Ph.D., chair of Molecular and Cellular Oncology. “Knockdown of ANG demonstrates its oncogenic role and decreases sensitivity to erlotinib treatment in vitro and in vivo. High plasma ANG level in patients is positively associated with their response to erlotinib treatment in a small patient cohort, highlighting the interplay between ANG and EGFR in PDAC.”

New understanding of ligand-receptor signaling

This oncogene “addiction” effect may be advantageous for development of a serum biomarker-guided targeted therapy in malignancies, said Hung. The ANG-EGFR axis also opens a new avenue toward better understanding of the ligand-receptor cognate signaling between RNases and RTKs, bridging two unrelated protein families with a previously unrecognized role of RNases.

EGFR is an effective target for anti-cancer therapies in certain clinical settings. Notably, EGFR tyrosine kinase inhibitors (TKIs) have been approved to treat both lung and pancreatic cancers. EGFR-activating mutations identified in lung cancers have been well demonstrated to predict response to EGFR-TKI, and EGFR-mutated lung cancers are often addicted to EFGR activation and sensitive to EGFR-TKI, resulting in prolonged lifespan in a number of lung cancer patients.

“However, those mutations are infrequent in PDAC,” said Hung. “EGRF-TKI erlotinib has shown only marginal benefit in general without any predictive biomarkers. Thus identification of predictive biomarkers for PDAC could benefit a subpopulation of patients who may be more likely to respond to erlotinib treatment.”

Creating a new model for therapy response

Hung’s team was able to present a model showing that higher levels of ANG observed in the pancreatic cancer microenvironment induces its binding to EGFR and activates EGFR signaling, resulting in tumorigenesis and increased erlotinib sensitivity. Specifically, they found that ANG increases endothelial cell migration and proliferation by initiating intracellular signaling pathways.

“Tumor-associated endothelial cells express high levels of EGFR, and EGFR signaling is required for their proliferation and angiogenesis,” said Hung, whose team believes that secretory ANG from endothelial cells may bind to EGFR and trigger EGFR signaling in tumor-associated endothelial cells.

The researchers also detected positive signals representing ANG in tumor cells, fibroblasts, macrophages, and endothelial cells, but not in lymphocytes or normal pancreas cells. Because EGFR is well established in the etiology of lung and PDAC, they believe it would be of interest to further determine whether the ANG-EGFR axis also exists in other tumor types.

“As pancreatic cancer is known to progress rapidly, it is critical to identify any predictive biomarkers to increase treatment efficacy,” said Hung. “Our results provide new insights into the ligand-receptor relationship between RTK and RNase families in intracellular transduction. Moreover, the pathological relevance between EGFR and secretory RNase in pancreatic cancer cells may have important clinical implications, given that the level of plasma ANG has the potential to serve as a non-invasive serum biomarker for erlotinib therapy.”