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CFTR modulation alter pancreatic cancer cell growth and signaling: implications for cancer risk in cystic fibrosis
Journal article   Peer reviewed

CFTR modulation alter pancreatic cancer cell growth and signaling: implications for cancer risk in cystic fibrosis

Yunxia O’Malley, Henry Keen, Ian M. Thornell, Zachary Campbell, Anna J. Prouty, Carlos H.F. Chan, Andrew W. Norris, Prabhat Goswami and Aliye Uc
Journal of cystic fibrosis
09/12/2026
DOI: 10.1016/j.jcf.2026.08.012
PMID: 42731950

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Abstract

•CFTR expression is markedly reduced in pancreas cancer tissues and cell lines compared to healthy controls.•CFTR restoration via ETI or adenoviral delivery reverses hyper-proliferative and migratory phenotypes in both CF and non-CF pancreatic cancer cell lines.•Rather than triggering apoptosis, ETI treatment downshifts cell cycle distribution kinetics and delays wound closure in vitro.•ETI suppresses key cell cycle regulators (CCNDs, CDKs, MCMs) and canonical Wnt pathway activators while upregulating pathway inhibitors.•These findings suggest a potential role for CFTR as a potential target for pancreatic cancer. People with cystic fibrosis (PwCF) have an increased risk of pancreatic cancer, likely related to chronic pancreatic inflammation and CFTR dysfunction. With the widespread use of CFTR modulators such as elexacaftor/tezacaftor/ivacaftor (ETI), understanding their impact on pancreatic ductal cell biology is critical. We studied human pancreatic ductal adenocarcinoma cell lines (PANC-1, CFPAC-1) and primary pig pancreatic duct epithelial cells with wild-type, F508del, or null CFTR. CFTR function was restored using adenoviral transfection (Ad5CMVCFTR-GFP) or ETI treatment. Proliferation was monitored longitudinally; cell cycle kinetics and active DNA synthesis were analyzed via Brdu/propidium iodide flow cytometry; cellular motility was assessed via scratch wound healing assays; apoptosis was measured by flow cytometry; CFTR activity was evaluated using halide-sensitive YFP; and gene expression was assessed by RT-qPCR and RNA sequencing. Human pancreas cancer CFTR expression was evaluated using public datasets. CFTR expression was reduced in pancreas cancer tissues, cell lines, and CF pancreatic duct epithelial cells compared to controls. CFTR-deficient cells exhibited increased baseline proliferation and migration. ETI treatment dynamically downshifted cell cycle distribution kinetics, without affecting apoptosis. Transcriptomic analysis revealed ETI downregulated key cell cycle regulators (CCNDs, CDKs, MCMs) and suppressed Wnt pathway activators while upregulating inhibitors, consistent with growth restriction. CFTR restoration not only improves channel function but also reprograms transcriptional networks to act as a synchronized brake on epithelial replication velocity and migration. These findings suggest that CFTR-targeting therapies may fundamentally influence pancreatic cancer biology and have implications for cancer risk management in PwCF.
 Cystic Fibrosis Pancreas CFTR modulators ETI

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