CF-causing mutations may drive growth of pancreatic cancer
Study finds CFTR modulators could slow this accelerated cell growth
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The genetic defect that causes cystic fibrosis (CF) may also directly contribute to the development of pancreatic cancer, a new study done in cell models suggests.
Researchers found that pancreatic cancer cells carrying CF-causing mutations grow faster than cancer cells without these mutations, and this growth could be slowed by treatment with CFTR modulators. The findings may help to explain why people with CF are at elevated risk of pancreatic cancer, as well as open up new avenues for potential treatment.
The study, “CFTR modulation alter pancreatic cancer cell growth and signaling: implications for cancer risk in cystic fibrosis,” was published in the Journal of Cystic Fibrosis.
Pancreatic cancer cells harboring mutation grow faster
CF is caused by mutations in the CFTR gene, which provides instructions to make a protein of the same name. The CFTR protein normally helps control the production of mucus; in CF, the protein is dysfunctional or entirely absent, which leads to the production of abnormally thick, sticky mucus. This mucus builds up in organs, including the lungs and the pancreas, and drives disease symptoms.
Previous studies have indicated that people with CF are at higher risk of pancreatic cancer than the general population. This has long been assumed to be because thick mucus in the pancreas drives inflammation, which sets the stage for the abnormal cell growth that characterizes cancer. But this new study suggests that CFTR mutations themselves, not just inflammation, may contribute to pancreatic cancer in people with CF.
“Our data provide mechanistic evidence that CFTR dysfunction itself may promote proliferative [growth-driving] signaling in [pancreas] cells,” the researchers wrote.
The scientists conducted a series of experiments in vitro, using cells grown in dishes. They found that pancreatic cancer cells harboring F508del, the most common CF-causing mutation, grow faster than cancer cells without this mutation. Cancer cells harboring CFTR mutations were also more mobile — a feature that helps tumors spread throughout the body.
Our study is the first to demonstrate direct inhibition of cancer cell proliferation through CFTR restoration in pancreas cancer and CF pancreatic epithelial cells. These results highlight CFTR as a potential tumor suppressor and suggest that its restoration may represent a novel therapeutic strategy.
Mutations in the CFTR gene similarly promoted growth and mobility in non-cancerous pancreatic cells. This suggests that a lack of functional CFTR may help drive the abnormal pancreatic cell growth that defines pancreatic cancer. Further supporting this idea, analyses of human tumor tissue indicated that CFTR protein expression is reduced in pancreatic tumors, even in people who don’t have CF.
“Our study demonstrates that CFTR expression is markedly reduced in human pancreas cancer tissues and cell lines, and that pancreatic … cells exhibit a highly proliferative and motile phenotype when CFTR is absent or dysfunctional,” the researchers wrote.
CFTR modulators are medications that can boost the functionality of the CFTR protein in people who carry certain mutations. A triple-combination modulator therapy called Trikafta (elexacaftor/tezacaftor/ivacaftor), which is sold by Vertex Pharmaceuticals, is widely approved for patients with F508del and other eligible mutations. In their cell models, the researchers found that treatment with Trikafta reduced the growth of pancreatic cancer cells.
“Our study is the first to demonstrate direct inhibition of cancer cell proliferation through CFTR restoration in pancreas cancer and CF pancreatic epithelial cells. These results highlight CFTR as a potential tumor suppressor and suggest that its restoration may represent a novel therapeutic strategy,” the researchers concluded.
The scientists stressed that this study was done in cell models, highlighting a need for additional work to see if similar mechanisms are also at play in living animals. Based on their findings, the researchers also called for proactive research to track pancreatic cancer outcomes in patients taking Trikafta and other modulators.
“Understanding the systemic impact of CFTR modulators is critical as [people with] CF live longer and face evolving health challenges, including malignancy [cancer] risk,” they wrote.
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