Pancreatic cancer remains one of the most lethal forms of cancer, with a five-year survival rate lingering in the single digits. As early detection remains rare and treatment options limited once the disease has progressed, efforts have increasingly turned toward prevention at the molecular level. A new study from Cold Spring Harbor Laboratory (CSHL), published in Cancer Research on April 2, 2025, identifies a promising strategy to delay or even prevent tumor formation by targeting two key cancer-related proteins: FGFR2 and EGFR.

Led by Dr. Claudia Tonelli and Dr. David Tuveson, the study demonstrates that inhibiting FGFR2, a known oncogene in several cancers, can significantly reduce pancreatic tumor development when applied at an early stage. When combined with inhibition of EGFR—another protein frequently overactive in pancreatic tumors—the preventive effect was even more pronounced.

Understanding the Genetic Landscape of Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, is characterized by a high prevalence of KRAS mutations, found in over 95% of cases. While KRAS is a well-established driver of tumorigenesis, the new findings reveal that FGFR2 acts as a crucial enhancer of KRAS signaling, thereby accelerating disease progression.

“We discovered that another gene, FGFR2, plays a role in enhancing mutant KRAS signaling in pancreatic cancer. When that happens, early pre-cancerous lesions become much more aggressive,” explains Tonelli, the study’s first author and a molecular medicine specialist.

Using mouse models and pancreatic organoids, the team observed that inhibition of FGFR2 at a critical early window led to delayed tumor growth. When EGFR was inhibited in parallel, the number of detectable pre-malignant lesions was significantly reduced, suggesting a synergistic effect between the two targets.

Implications for Early Intervention

This research introduces the concept of cancer interception—identifying and suppressing early oncogenic events before clinical cancer develops. Importantly, both FGFR2 and EGFR inhibitors are already in clinical use for other malignancies, offering a potentially fast translation to human trials in high-risk populations.

“Patients with a family history of pancreatic cancer would likely be among the first candidates to receive such treatments,” Tonelli notes. The results provide a rationale for preventive therapies in genetically predisposed individuals, particularly those with known KRAS mutations or hereditary risk factors.

Funding and Publication Details

This study was supported by the National Institutes of Health, The Lustgarten Foundation, Thompson Family Foundation, Pershing Square Foundation, Simons Foundation, Cold Spring Harbor Laboratory Association, American-Italian Cancer Foundation, and Northwell Health.

Citation:
Tonelli, C., et al. FGFR2 Abrogation Intercepts Pancreatic Ductal Adenocarcinoma Development. Cancer Research, 2 April 2025. DOI: 10.1158/0008-5472.CAN-24-4576