Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, driven by complex genetic, epigenetic, and microenvironmental factors. Recent findings implicate the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel in CRC progression, as CFTR levels are notably reduced in sporadic CRCs, particularly in advanced and metastatic tumors, correlating with poorer patient outcomes. Additionally, cystic fibrosis (CF) patients, who carry CFTR mutations, have a 6-fold increased risk of early-onset CRC. Given recent advances in small-molecule modulators that restore CFTR function in CF patients, this study explored the potential of repositioning these modulators to address CFTR downregulation in sporadic CRC.

Using a panel of CRC cell lines, we investigated whether CFTR modulators can increase CFTR functional expression in cells with various genetic backgrounds and whether such improvements could reduce their oncogenic properties.

Our data show that treatment with the CFTR folding correctors VX-661 and VX-445 led to a significant, approximately three-fold increase in CFTR abundance in CRC cells expressing reduced but detectable levels of the channel. Additionally, these treatments significantly reduced the migratory and invasive behavior of Caco-2 and DLD-1 cells, particularly when combined with the CFTR potentiator VX-770.

Our findings suggest that CFTR modulators may hinder the oncogenic properties of CRC cells. Further in vivo studies are necessary to fully assess their potential benefits for repositioning as a CRC treatment.