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.

细胞身份的变化（也称为组织学转化或谱系可塑性）可能会导致许多癌症（包括肺腺癌（LUAD））的恶性进展和治疗耐药。谱系特异性转录因子 FoxA1 和 FoxA2 (FoxA1/2) 控制 NKX2-1/TTF1 阴性 LUAD 中的身份。然而，它们在 NKX2-1 阳性 LUAD 中的作用尚未得到系统研究。我们发现Foxa1/2敲除严重损害 KRAS 驱动的基因工程小鼠模型和人类细胞系的肿瘤发生。FoxA1/2 的缺失会导致双重身份状态的崩溃，其特征​​是肺部和胃肠道转录程序的共表达，这与 LUAD 的进展有关。从机制上讲，FoxA1/2 缺失会导致 NKX2-1 活性和基因组定位异常，进而积极抑制肿瘤发生并驱动与非增殖状态相关的替代细胞识别程序。这项工作表明 FoxA1/2 表达是 NKX2-1 阳性 LUAD 中的谱系特异性脆弱性，并确定了该疾病中针对 FoxA1/2 的反应和耐药机制。