Ductal pancreatic cancer interception by FGFR2 abrogation
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Abstract:
Activating KRAS mutations are a key feature of pancreatic ductal adenocarcinoma (PDA) and drive tumor initiation and progression. However, mutant KRAS by itself is weakly oncogenic. The pathways that cooperate with mutant KRAS to induce tumorigenesis are less-defined. Analyzing organoids and murine and human pancreatic specimens, we found that the receptor tyrosine kinase FGFR2 was progressively up-regulated in mutant KRAS-driven metaplasia, pre-neoplasia and Classical PDA. Using genetic mouse models, we showed that FGFR2 supported mutant KRAS-driven transformation of acinar cells by promoting proliferation and MAPK pathway activation. FGFR2 abrogation significantly delayed tumor formation and extended the survival of these mice. Furthermore, we discovered that FGFR2 collaborated with EGFR and dual blockade of these receptor signaling pathways significantly reduced mutant KRAS-induced pre-neoplastic lesion formation. Together, our data have uncovered a pivotal role for FGFR2 in the early phases of pancreatic tumorigenesis, paving the way for future therapeutic applications of FGFR2 inhibitors for pancreatic cancer interception.
Statement Of Significance:
Mutant KRAS-expressing pancreatic intraepithelial neoplasias (PanINs), the precursor lesions of PDA, are prevalent in the average healthy adult but rarely advance to invasive carcinoma. Here, we discovered that FGFR2 promoted PDA progression by amplifying mutant KRAS signaling and that inactivation of FGFR2 intercepted disease progression.
Insights
Fibroblast growth factor receptor 2 (FGFR2) drives pancreatic ductal adenocarcinoma (PDA) by amplifying KRAS signaling. Blocking FGFR2 intercepts PDA progression, offering a potential therapeutic strategy for early pancreatic cancer.
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.
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