HNF4α controls growth, identity, and KRAS inhibitor response in 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), 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 promoted IMA growth and activated a gastric pit cell-like program. Loss of HNF4α enabled forkhead box A1 and A2 (FoxA1/2) transcription factors to bind de novo sites and activate alternative, nongastric identities in IMA. HNF4α also established a mucinous program associated with tolerance to KRAS blockade, and loss of HNF4α enhanced response to KRASG12D inhibition. Mechanistically, HNF4α blocked cell-cycle exit in drug-tolerant persister cells and promoted activity of the antioxidant transcription factor nuclear factor erythroid 2-related factor 2 (NRF2). NRF2 activation partially rescued the effects of Hnf4a deletion on KRASG12D inhibition, whereas NRF2 inhibition enhanced sensitivity to KRASG12D blockade. Thus, HNF4α is a key regulator of growth, identity, and primary response to KRASG12D inhibition in IMA.