FOXA2 drives lineage plasticity and KIT pathway activation in neuroendocrine prostate cancer

Prostate cancer adeno-to-neuroendocrine lineage transition has emerged as a mechanism of targeted ther-apeutic resistance. Identifying the direct molecular drivers and developing pharmacological strategies using clinical-grade inhibitors to overcome lineage transition-induced therapeutic resistance are imperative. Here, using single-cell multiomics analyses, we investigate the dynamics of cellular heterogeneity, transcriptome regulation, and microenvironmental factors in 107,201 cells from genetically engineered mouse prostate can-cer samples with complete time series of tumor evolution seen in patients. We identify that FOXA2 orches-trates prostate cancer adeno-to-neuroendocrine lineage transition and that Foxa2 expression is significantly induced by androgen deprivation. Moreover, Foxa2 knockdown induces the reversal of adeno-to-neuroen-docrine transition. The KIT pathway is directly regulated by FOXA2 and specifically activated in neuroendo-crine prostate cancer (NEPC). Pharmacologic inhibition of KIT pathway significantly suppresses mouse and human NEPC tumor growth. These findings reveal that FOXA2 drives adeno-to-neuroendocrine lineage plas-ticity in prostate cancer and provides a potential pharmacological strategy for castration-resistant NEPC.