Ductal pancreatic cancer interception by FGFR2 abrogation

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• Activating KRAS mutations are central to pancreatic ductal adenocarcinoma (PDA) but require cooperating pathways for tumorigenesis.
• The specific pathways collaborating with mutant KRAS in early pancreatic cancer remain incompletely understood.

Purpose of the Study:

• To investigate the role of receptor tyrosine kinases in cooperating with mutant KRAS during pancreatic cancer initiation and progression.
• To identify potential therapeutic targets for early-stage pancreatic cancer interception.

Main Methods:

• Analysis of organoids, murine, and human pancreatic specimens.
• Utilized genetic mouse models to study FGFR2 function in vivo.
• Investigated the effects of FGFR2 and EGFR signaling blockade.

Main Results:

• Fibroblast growth factor receptor 2 (FGFR2) expression is progressively upregulated in mutant KRAS-driven pancreatic metaplasia, pre-neoplasia, and PDA.
• FGFR2 supports mutant KRAS-driven acinar cell transformation by enhancing proliferation and MAPK pathway activation.
• FGFR2 inactivation significantly delayed tumor formation and improved survival in mouse models.
• Dual blockade of FGFR2 and EGFR signaling markedly reduced mutant KRAS-induced pre-neoplastic lesions.

Conclusions:

• FGFR2 plays a critical role in the early stages of pancreatic tumorigenesis by amplifying mutant KRAS signaling.
• Inactivation of FGFR2 effectively intercepts pancreatic cancer progression.
• FGFR2 inhibitors represent a promising therapeutic avenue for pancreatic cancer interception.