HNF4α controls growth, identity and response to KRAS inhibition of invasive mucinous adenocarcinoma of the lung

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), NKX2-1 loss triggers a pulmonary to gastric switch marked by aberrant activation of HNF4α, a master regulator of gastrointestinal/hepatic differentiation. We find that HNF4α promotes IMA growth and activates a gastric pit cell-like program. Hnf4a deletion induces IMA dedifferentiation, enabling FoxA1/2 to access de novo sites and activate alternative identities. HNF4α also induces a mucinous program associated with tolerance to KRAS blockade, and HNF4α loss 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 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 identity and primary response to KRAS ^G12D inhibition in IMA.