Protein Blocking Effectiveness of Vertex’s Experimental CF Therapy Lumacaftor Discovered

Despite every effort to design a drug effective in helping cystic fibrosis patients with defective CFTR proteins, sometimes drugs are thwarted by mechanisms orchestrated by other proteins within cells. A group of researchers from the Department of Human Genetics at National Health Institute Doutor Ricardo Jorge in Portugal recently published in Science Signaling an article that identified a mechanism behind resistance to treatment by Vertex Pharmaceuticals’ VX-809.

Proteins in cells that remove improperly folded proteins, such as CFTR protein, from the cell membrane are called peripheral protein quality control (PPQC) checkpoint proteins. The PPQC checkpoint uses a mechanism orchestrated by a proteasome known as E3 ubiquitin ligase CHIP (short for carboxyl terminus of Hsc70 interacting protein) that degrades proteins. As explained in the article, “A Molecular Switch in the Scaffold NHERF1 Enables Misfolded CFTR to Evade the Peripheral Quality Control Checkpoint,” PPQC negates the benefits of VX-809, a therapy that helps traffic CFTR protein to the cell membrane in patients diagnosed with F508del-CFTR, because the protein is recognized as improperly folded.

The team used an in vitro culture of epithelial cells mutated to express F508del-CFTR. Cells were treated with VX-809, and then the researchers determined whether or not PPQC was able to recognize the improperly folded CFTR protein that was brought to the membrane surface. The team determined that the scaffold protein NHERF1 (short for Na⁺/H⁺ exchange regulatory factor 1) adopts a conformation that regulates PPQC checkpoint.

The researchers also found that when another scaffold protein, Rac1, is activated, the efficacy of VX-809 is nearly tripled. These results are negated by interfering with the association of NHERF1 with another adaptor protein known as ezrin. “Thus, rather than mainly directing anchoring of F508del-CFTR to the actin cytoskeleton, induction of ezrin activation by Rac1 signaling triggered a conformational change in NHERF1, which was then able to bind and stabilize misfolded CFTR at the plasma membrane,” stated the authors. “These insights into the cell surface stabilization of CFTR provide new targets to improve treatment of cystic fibrosis.”

Implications of this research include techniques that increase the effectiveness of therapies directed towards treating patients with cystic fibrosis. Perhaps if a medication is designed to activate Rac1, a clinical trial that combines this experimental therapy with VX-809 could be tested in patients with cystic fibrosis to expand the reach of this drug.