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

Raymond Ho1,2, Jason C Mills1

  • 1Department of Molecular and Precision Medicine, Penn State College of Medicine, Hershey, Pennsylvania, USA.

The Journal of Clinical Investigation
|July 1, 2026
PubMed

Insights

Hepatocyte nuclear factor 4 alpha (HNF4α) drives lung cells to adopt gastric features, promoting resistance to KRAS inhibition. This cellular plasticity mechanism is implicated in invasive mucinous adenocarcinoma (IMA) and suggests new therapeutic targets.

Area of Science:

  • Cellular plasticity
  • Cancer biology
  • Molecular mechanisms of tumorigenesis

Background:

  • Cellular plasticity enables lineage changes for tissue repair but can drive cancer development.
  • Invasive mucinous adenocarcinoma (IMA) arises from lung epithelial cells reprogramming into gastric-like cells.
  • Understanding the molecular drivers of this reprogramming is crucial for therapeutic development.

Purpose of the Study:

  • To elucidate the role of hepatocyte nuclear factor 4 alpha (HNF4α) in lung epithelial cell reprogramming towards gastric identity.
  • To investigate the mechanism by which HNF4α influences transcription factors FOXA1 and FOXA2.
  • To determine HNF4α's impact on resistance to KRAS inhibition and its link to nuclear factor erythroid 2-related factor 2 (NRF2) activity.

Main Methods:

  • Investigated the role of HNF4α in lung epithelial cells.
  • Analyzed the interaction of HNF4α with FOXA1 and FOXA2 transcription factors at gastric gene enhancer loci.
  • Assessed the effect of HNF4α on NRF2 activity and resistance to KRAS inhibition.

Main Results:

  • HNF4α promotes gastric identity in lung epithelial cells.
  • HNF4α restricts FOXA1 and FOXA2 to gastric gene enhancer loci.
  • HNF4α enhances resistance to KRAS inhibition by upregulating NRF2 activity.

Conclusions:

  • HNF4α is a key regulator of cellular plasticity driving lung-to-gastric reprogramming in IMA.
  • The HNF4α-FOXA axis and HNF4α-NRF2 pathway are critical for IMA development and therapeutic resistance.
  • Targeting HNF4α or its downstream pathways may offer novel therapeutic strategies for IMA.

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