FoxA1 and FoxA2 control growth and cellular identity in NKX2-1-positive lung adenocarcinoma

Changes in cellular identity (also known as histologic transformation or lineage plasticity) can drive malignant progression and resistance to therapy in many cancers, including lung adenocarcinoma (LUAD). The lineage-specifying transcription factors FoxA1 and FoxA2 (FoxA1/2) control identity in NKX2-1/TTF1-negative LUAD. However, their role in NKX2-1-positive LUAD has not been systematically investigated. We find that Foxa1/2 knockout severely impairs tumorigenesis in KRAS-driven genetically engineered mouse models and human cell lines. Loss of FoxA1/2 leads to the collapse of a dual-identity state, marked by co-expression of pulmonary and gastrointestinal transcriptional programs, which has been implicated in LUAD progression. Mechanistically, FoxA1/2 loss leads to aberrant NKX2-1 activity and genomic localization, which in turn actively inhibits tumorigenesis and drives alternative cellular identity programs that are associated with non-proliferative states. This work demonstrates that FoxA1/2 expression is a lineage-specific vulnerability in NKX2-1-positive LUAD and identifies mechanisms of response and resistance to targeting FoxA1/2 in this disease. [Display omitted] •FoxA1 and FoxA2 are required for growth in NKX2-1-positive lung adenocarcinoma•FoxA1 and FoxA2 activate a dual-identity cellular state critical in lung adenocarcinoma tumor evolution•FoxA1 and FoxA2 suppress non-proliferative cellular states driven by novel NKX2-1 activity•NKX2-1 actively represses growth following Foxa1/2 deletion Lung adenocarcinoma (LUAD) evolution relies on epigenetic changes that confer increased lineage plasticity. Orstad et al. show that transcription factors FoxA1 and FoxA2 are critical drivers of LUAD growth and transcriptional evolution. FoxA1 and FoxA2 restrain the activity of NKX2-1; following Foxa1/2 deletion, NKX2-1 actively inhibits tumor growth by promoting non-proliferative cell fates.