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HNF4α controls growth, identity, and KRAS inhibitor response in invasive mucinous adenocarcinoma of the lung

Headtlove Essel Dadzie,¹ Yangsook Song Green,¹ Soledad Camolotto,¹ Henry U. Arnold,¹ Matthew Gumbleton,¹ Minzhe Guo,² Mari Mino-Kenudson,³ Yutaka Maeda,² Benjamin T. Spike,¹ and Eric L. Snyder¹

Published May 12, 2026 - More info

Cellular plasticity is a hallmark of cancer, enabling tumor cells to alter identity and evade therapeutic pressure. In invasive mucinous adenocarcinoma of the lung (IMA), NK2 homeobox 1 (NKX2-1) loss triggers a pulmonary to gastric switch marked by aberrant activation of hepatocyte nuclear factor 4 alpha (HNF4α), a master regulator of gastrointestinal/hepatic differentiation. We show that HNF4α promotes IMA growth and activates a gastric pit cell-like program. Loss of HNF4α enables forkhead box A1/A2 (FoxA1/2) transcription factors to bind de novo sites and activate alternative, non-gastric identities in IMA. HNF4α also establishes a mucinous program associated with tolerance to KRAS blockade, and loss of HNF4α enhances response to KRAS^G12D inhibition. Mechanistically, HNF4α blocks cell cycle exit in drug-tolerant persister cells and promotes activity of the antioxidant transcription factor nuclear factor erythroid 2-related factor 2 (NRF2). NRF2 activation partially rescues effects of Hnf4a deletion on KRAS^G12D inhibition, whereas NRF2 inhibition enhances sensitivity to KRAS^G12D blockade. Thus, HNF4α is a key regulator of growth, identity, and primary response to KRAS^G12D inhibition in IMA.

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