FoxA1 and FoxA2 regulate 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 multiple types of cancer, including lung adenocarcinoma (LUAD). The lineage specifying transcription factors FoxA1 and FoxA2 (FoxA1/2) regulate 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. Foxa1/2 deletion 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, loss of FoxA1/2 leads to aberrant NKX2-1 activity and genomic localization, which inhibits tumorigenesis and drives alternative cellular identity programs associated with non-proliferative states. This work demonstrates that FoxA1/2 expression is a novel lineage-specific vulnerability in NKX2-1-positive LUAD and identifies mechanisms of response and resistance to targeting FoxA1/2 in this disease. SIGNIFICANCE Recent advances in targeted protein degradation have the potential to make transcription factor inhibition a tractable therapeutic strategy in cancer. This study shows that targeting FoxA1/2 may have a major impact on NKX2-1-positive lung adenocarcinoma, including tumors driven by currently undruggable KRAS mutants. ### Competing Interest Statement CRV has received consulting fees from Flare Therapeutics, Roivant Sciences, and C4 Therapeutics, has served on the scientific advisory board of KSQ Therapeutics, Syros Pharmaceuticals, and Treeline Biosciences, has received research funding from Boehringer-Ingelheim and Treeline Biosciences, and owns a stock option from Treeline Biosciences.