The combination elexacaftor/tezacaftor/ivacaftor (ETI) modulates the de novo synthethic pathway of ceramides in a genotype-independent manner

J Cyst Fibros. 2023 Jul;22(4):680-682. doi: 10.1016/j.jcf.2023.04.012. Epub 2023 Apr 21.

Abstract

We report here how the triple combination of drugs elexacaftor/tezacaftor/ivacaftor (ETI) alters the balance of the de-novo synthethic pathway of sphingolipids in primary cells of human bronchial epithelium. The treatment with ETI roughly doubles the levels of dihydrosphingolipids, possibly by modulating the delta(4)-desaturase enzymes that convert dihydroceramides into ceramides. This appears to be an off-target effect of ETI, since it occurs in a genotype-independent manner, for both cystic fibrosis (CF) and non-CF subjects.

Keywords: Cystic Fibrosis; dihydroceramides; lipidomics; off-target effect; sphingolipids; triple combination ETI.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminophenols
  • Benzodioxoles
  • Ceramides
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics
  • Cystic Fibrosis* / drug therapy
  • Cystic Fibrosis* / genetics
  • Genotype
  • Humans
  • Mutation

Substances

  • elexacaftor
  • ivacaftor
  • tezacaftor
  • Ceramides
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Benzodioxoles
  • Aminophenols