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

Change in cancer cell identity is well characterized as a mechanism of cancer progression and acquired resistance to targeted therapies. Lung adenocarcinoma (LUAD) exhibits significant heterogeneity in cell identity and differentiation state; these characteristics correlate directly with prognosis, response to available therapies, and acquisition of drug resistance. In previous work, we have shown that FoxA1 and FoxA2 (FoxA1/2) activate a gastric differentiation program in NKX2-1-negative LUAD. Here we investigate the role of FoxA1/2 in NKX2-1-positive LUAD. We find that FoxA1/2 are consistently expressed in NKX2-1-positive human LUAD. Foxa1/2 deletion severely impairs proliferation and significantly prolongs overall survival in a genetically engineered mouse model of KRAS-driven LUAD. FoxA1/2 activate expression of a mixed-lineage transcriptional program characterized by co-expression of pulmonary (Alveolar Type II) and gastrointestinal marker genes. Loss of FoxA1/2 causes a lineage switch, activating gene expression programs associated with Alveolar Type I cells and maturing squamous epithelial cells. Inhibition of NKX2-1 partially rescues the antiproliferative impact of FoxA1/2 loss, showing that NKX2-1 retains some degree of activity in FoxA1/2-null cells, despite its inability to activate canonical target genes. In summary, this study identifies FoxA1/2 expression as a novel vulnerability in NKX2-1 positive LUAD and shows that FoxA1/2 actively regulate cellular identity in this disease.