Deletion of phenylalanine at position 508 (F508del) in cystic fibrosis 
transmembrane conductance regulator (CFTR) is the most common cystic fibrosis 
(CF)-causing mutation. Recently, ORKAMBI, a combination therapy that includes a 
corrector of the processing defect of F508del-CFTR (lumacaftor or VX-809) and a 
potentiator of channel activity (ivacaftor or VX-770), was approved for CF 
patients homozygous for this mutation. However, clinical studies revealed that 
the effect of ORKAMBI on lung function is modest and it was proposed that this 
modest effect relates to a negative impact of VX-770 on the stability of 
F508del-CFTR. In the current studies, we showed that this negative effect of 
VX-770 at 10 μM correlated with its inhibitory effect on VX-809-mediated 
correction of the interface between the second membrane spanning domain and the 
first nucleotide binding domain bearing F508del. Interestingly, we found that 
VX-770 exerted a similar negative effect on the stability of other membrane 
localized solute carriers (SLC26A3, SLC26A9, and SLC6A14), suggesting that this 
negative effect is not specific for F508del-CFTR. We determined that the 
relative destabilizing effect of a panel of VX-770 derivatives on F508del-CFTR 
correlated with their predicted lipophilicity. Polarized total internal 
reflection fluorescence microscopy on a supported lipid bilayer model shows that 
VX-770, and not its less lipophilic derivative, increased the fluidity of and 
reorganized the membrane. In summary, our findings show that there is a 
potential for nonspecific effects of VX-770 on the lipid bilayer and suggest 
that this effect may account for its destabilizing effect on VX-809- rescued 
F508del-CFTR.