Blocking FGFR2 may stop pancreatic cancer from developing
Targeting protein may have implications for PDAC treatment
Blocking the activity of a protein called FGFR2 may prevent some pancreatic cancers from developing, a study in mice indicated.
The study, “FGFR2 Abrogation Intercepts Pancreatic Ductal Adenocarcinoma Development,” was published in the American Association for Cancer Research journal Cancer Research. The work was supported by the National Institutes of Health and the Lustgarten Foundation.
“Understanding the additional pathways that promote progression from a precancerous pancreatic lesion to a malignant tumor could help identify more viable treatment strategies as well as cancer interception approaches to stop PDAC [pancreatic ductal adenocarcinoma, the most common form of pancreatic cancer] from developing in the first place,” study co-author Claudia Tonelli, PhD, a research investigator at Cold Spring Harbor Laboratory, said in an association news story.
PDAC develops from precancerous lesions in the pancreas, but only a fraction of these lesions will turn into cancer. The processes by which these precancerous lesions grow into a malignant tumor aren’t fully understood.
PDAC and its precancerous lesions often carry mutations that affect a protein called KRAS, but available data suggest that mutant KRAS alone isn’t enough to drive the change from precancerous lesion to PDAC.
Link to KRAS
Tonelli and colleagues analyzed mouse models of PDAC as well as human tissue samples. They found that FGFR2 expression, a signaling protein involved in regulating cell growth, was elevated in KRAS-mutated precancerous lesions and certain KRAS-mutated PDAC samples.
The researchers noted that, in mouse models, higher FGFR2 levels in precancerous lesions were associated with increased KRAS signaling in those lesions.
“We know that precancerous pancreatic lesions often carry KRAS mutations,” Tonelli said. “Our observation that FGFR2 expression was associated with increased KRAS signaling suggests that FGFR2 may play a key role in driving the progression of KRAS-mutated precancerous lesions to malignancy.”
Spurred by this finding, the researchers engineered KRAS-mutant mice so that they could not produce the FGFR2 protein. In these mice lacking FGFR2, pancreatic tumors took more time to form and grew slower, and the mice consequently lived longer.
“These data have uncovered a pivotal role for FGFR2 in the early phases of pancreatic [tumor development], paving the way for future therapeutic applications of FGFR2 inhibitors for pancreatic cancer interception,” the researchers wrote.
Further investigation showed that FGFR2 interacts with another signaling molecule called EGFR. Blocking the activity of FGFR2 and EGFR simultaneously reduced the formation of precancerous lesions in the lab models.
“Our study provides critical insights into pancreatic cancer development and could guide the development of strategies for the interception and prevention of pancreatic malignancies,” Tonelli said.
The scientists said targeting FGFR2 may be a viable strategy to stop precancerous lesions from progressing to full-blown cancer, though they stressed that further tests and clinical trials are needed to confirm this idea.
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