Cellular plasticity as a therapeutic vulnerability: HNF4α is a key target in lung adenocarcinoma

Cells use plasticity programs to change lineages, which aids in tissue regeneration and remodeling but also allows aberrant cells to become cancerous and escape therapy. For example, tumor cells in invasive mucinous adenocarcinoma (IMA) emerge from lung epithelial cells by a plasticity program that reprograms them into gastric epithelium–like cells. In this issue of the JCI , Dadzie et al. show that hepatocyte nuclear factor 4 α (HNF4α) promotes gastric identity in lung epithelial cells via a mechanism involving restriction of FOXA1 and FOXA2 transcription factors to gastric gene enhancer loci. HNF4α also promotes resistance to KRAS inhibition by increasing nuclear factor erythroid 2–related factor 2 (NRF2) activity. These findings may advance therapeutic avenues in IMA.