ASCL1 is activated downsrteam of ROR2/CREB signaling pathway to support lineage plasticity [ChIP-seq]

Lineage plasticity has been shown to be a form of therapy-induced drug resistance. In prostate cancer, androgen receptor (AR) pathway inhibitors have led to accretion of tumor relapse with loss of AR signaling and a shift from a luminal state to an alternate program. Although different genomic and epigenomic aberrations have been correlated with lineage reprogramming, the molecular and signaling mechanisms orchestrating the development of lineage plasticity under the pressure of AR-targeted therapies are not fully understood. Here, a survey of receptor tyrosine kinases (RTKs) identified ROR2 as the top-upregulated RTK following AR pathway inhibition, which feeds into lineage plasticity by promoting stem cell-like and neuronal networks. Mechanistically, we demonstrated that ROR2 activates the ERK/CREB signaling pathway to modulate the expression of the lineage commitment transcription factor, ASCL1. Collectively, our findings nominate ROR2 as a potential therapeutic target to reverse the ENZ-induced plastic phenotype and potentially re-sensitize tumors to AR pathway inhibitors. ChIP-seq for AR in 16D cell line with or without DHT treatment, ChIP-seq for H3K27Ac in 16D and NCI-H660