Pancreatic ductal adenocarcinoma, the most common type of pancreatic cancer, is also among the most deadly, with an average 5-year survival rate of less than 10%. The malignancy is often preceded by precancerous lesions. Traditional treatments of the cancer, including chemotherapy, surgery, and radiation therapy, have not been shown to significantly improve survival outcomes.
In a recent preclinical study, FGFR2 inhibition reduced mutant KRAS signaling, delaying the development of KRAS-mutant pancreatic ductal adenocarcinoma in mice. The results may guide the development of future strategies for the interception and prevention of pancreatic malignancies. The study by Tonelli et al was published in Cancer Research.
Study Methodology and Results
The researchers analyzed murine and human pancreatic tissue specimens. They found that, compared with normal tissue, FGFR2 expression was higher in KRAS-mutant precancerous lesions and some KRAS-mutant pancreatic ductal adenocarcinomas. Of note, they found that FGFR2 expression in murine precancerous lesions correlated with an increase in mutant KRAS signaling.
They also found significantly fewer precancerous lesions and delayed formation of pancreatic ductal adenocarcinomas in KRAS-mutant mice in which the FGFR2 gene had been deleted compared with those mice with an intact FGFR2 gene. Furthermore, the combined inhibition of FGFR2 and another signaling protein, EGFR, significantly reduced the development of precancerous lesions in mice carrying mutated KRAS.
“With the increasing number of FGFR2 inhibitors entering the clinic, this study lays the foundation to explore the potential use of these compounds in combination with EGFR inhibitors for [pancreatic ductal adenocarcinoma] interception. However, further work is required to determine the target population with high risk of developing pancreatic cancer that should receive these therapies and potential adaptive escape mechanisms associated with the redundancy of [receptor tyrosine kinase] signaling,” concluded the study authors.
“Our study provides critical insights into pancreatic cancer development and could guide the development of strategies for the interception and prevention of pancreatic malignancies,” said Claudia Tonelli, PhD, a research investigator in the Tuveson Lab at Cold Spring Harbor Laboratory in Cold Spring Harbor, New York, and lead author of this study, in a statement.
David A. Tuveson, MD, PhD, FAACR, of Cold Spring Harbor Laboratory, is the corresponding author of the Cancer Research article.
Disclosure: Funding for this study was provided by the National Institutes of Health and the Lustgarten Foundation. For full disclosures of the study authors, visit aacrjournals.org/cancerres.
