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Poster: 334CFTR modulators decrease cellular metabolism and proliferation in pancreatic cancer cell lines
Abstract   Peer reviewed

Poster: 334CFTR modulators decrease cellular metabolism and proliferation in pancreatic cancer cell lines

Y. O'Malley, J. Davelaar, A. Prouty, A. Jain, H. Keen, I. Thornell, A. Norris and A. Uc
Journal of cystic fibrosis, Vol.25, pp.169-169
09/2026
DOI: 10.1016/j.jcf.2026.07.364

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) risk is increased in people with cystic fibrosis (PwCF), and germline CFTRmutations are present in up to 12% of PDAC cases, implicating CFTR dysfunction in pancreatic tumorigenesis. CFTR modulators, including elexacaftor/tezacaftor/ivacaftor (ETI), are now standard therapy for cystic fibrosis; however, their long-term effects on pancreatic cancer biology remain poorly defined. We previously demonstrated that ETI inhibits cell cycle progression in CF-derived pancreatic cells. Given the central role of metabolic reprogramming in PDAC, we hypothesized that CFTR modulation may suppress pancreatic cancer growth by altering cellular bioenergetics. Human PDAC cell lines expressing endogenous CFTR (PANC-1, AsPC-1, BxPC-3, and SW1990) and a homozygous CFTR F508del cell line (CFPAC-1) were cultured as monolayers and as organoids embedded in Matrigel. Cell proliferation was assessed by monolayer cell counts over 15–20 days and by quantification of organoid surface area using ImageJ. Cell migration was evaluated using scratch wound assays. CFTR functional activity was measured using a halide-sensitive YFP assay. Mitochondrial respiration and ATP production were analyzed using Seahorse XF Mito Stress and ATP Production assays. Global transcriptional changes were assessed by bulk RNA sequencing, with pathway-level analyses performed using Advaita Bioinformatics software. ETI increased CFTR function and suppressed CFPAC-1 cell proliferation and migration (p < 0.05–0.001), with effects that were reversible upon drug withdrawal. ETI also inhibited growth in non-CF PDAC cell lines, including PANC-1, AsPC-1, BxPC-3, and SW1990. Mitochondrial stress and ATP rate analyses revealed that ETI treatment reduced basal and maximal mitochondrial respiration, ATP production-linked oxygen consumption, spare respiratory capacity, coupling efficiency, and non-mitochondrial oxygen consumption in both CFPAC-1 and PANC-1 cells, while proton leak remained unchanged. These findings indicate a coordinated downregulation of cellular energy production without disruption of mitochondrial membrane integrity. Consistent with this metabolic phenotype, RNA sequencing demonstrated reduced expression of genes involved in glycolysis, the tricarboxylic acid cycle, and oxidative phosphorylation. ETI induces broad metabolic reprogramming characterized by reduced mitochondrial respiration and ATP production, leading to decreased proliferative and migratory capacity in PDAC cells. These findings suggest cellular energetics as a potential mechanistic link between CFTR modulation and pancreatic cancer growth suppression as a previously unrecognized role for CFTR modulators. This work may have important implications for CF associated pancreatic disease and malignancy and raises the possibility that CFTR-targeted therapies may influence pancreatic cancer biology beyond the context of CF.

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