Cellular plasticity as a therapeutic vulnerability: HNF4α is a key target in lung adenocarcinoma
Raymond Ho, Jason C. Mills
Raymond Ho, Jason C. Mills
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Cellular plasticity as a therapeutic vulnerability: HNF4α is a key target in lung adenocarcinoma

Abstract

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.

Authors

Raymond Ho, Jason C. Mills

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Figure 1

HNF4α drives plasticity and resistance to KRAS inhibition in IMA.

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HNF4α drives plasticity and resistance to KRAS inhibition in IMA. Dadzie...
Dadzie et al. (9) identified mechanisms governing plasticity and therapeutic resistance in IMA, a subtype of lung cancer characterized by loss of NKX2-1 and KRAS mutations. (A) They have shown that HNF4α cooperates with the pioneer transcription factors FOXA1/2 to promote IMA growth and gastric identity. (B) In the absence of HNF4α, FOXA1/2 bind to nongastric gene loci, and IMA growth is slowed. cKO, conditional KO. (C) Dadzie et al. also found that HNF4α stabilizes the NRF2 protein through regulation of its ubiquitination, which promotes resistance to KRAS inhibition. When NRF2 protein expression is low, IMA sensitivity to such therapy is increased.