A NEW study reveals why certain cystic fibrosis (CF) variants fail to respond to current drug therapies, shedding light on hidden structural instabilities within a key domain of the CFTR protein. The findings, based on high-throughput proteomic profiling and computational modeling, could help expand treatment options for a subset of CF patients currently left behind by available therapies.
Cystic fibrosis is a life-shortening genetic disorder caused by mutations in the CFTR gene, which impair the function of an anion channel critical for fluid regulation in the lungs and other organs. While a class of small molecules known as “correctors” has improved outcomes for many patients by enhancing the folding and trafficking of the misfolded CFTR protein, nearly 3% of individuals with CF carry variants that remain poorly responsive to these drugs.
Researchers in this study applied affinity purification mass spectrometry to examine how different CFTR variants interact with the cellular protein folding machinery, or “proteostasis” network, under drug treatment. Variants that responded well to correction showed similar patterns of proteostasis remodeling. However, poorly responsive variants diverged, exhibiting incomplete engagement of protein quality control systems and only partial correction.
Further structural modeling pinpointed the source of this drug resistance to instability in the first nucleotide-binding domain (NBD1) of the CFTR protein. The commonly used corrector VX-445 was insufficient to stabilize NBD1 in these poorly responsive variants. Notably, introducing secondary mutations designed to reinforce NBD1 structure successfully rescued the folding and trafficking defects, restoring drug responsiveness.
These findings highlight NBD1 as a critical structural bottleneck in the treatment of difficult CFTR variants. By mapping distinct proteostasis landscapes and identifying correctable vulnerabilities, the study opens the door to mechanism-driven drug development for CF patients who currently lack effective options.
Reference:
McDonald EF et al. Proteostasis landscapes of cystic fibrosis variants reveal drug response vulnerability. Proc Natl Acad Sci U S A. 2025;122(17):e2418407122.
