ZNF274 constrains lineage plasticity and drives intrinsic resistance to CDK7 inhibitors in pancreatic cancer

Pancreatic Ductal Adenocarcinoma (PDAC) is characterized by two distinct transcriptional subtypes: classical and basal, which may interconvert. We show the KRAB-ZNF protein, ZNF274, correlates with PDAC subtype and regulates sensitivity to CDK7 inhibition by facilitating heterochromatin maintenance and gene suppression. We find ZNF274 loss drives a classical to basal transition, induces invasive protrusions and facilitates invasion capacity. We define two mechanistic arms to this regulation. ZNF274 directly suppresses ZEB1 expression. When ZNF274 is lost, ZEB1 facilitates acquisition of mesenchymal features, keratin gene expression, and susceptibility to CDK7 inhibition. Second, ZNF274 dampens expression of repetitive elements including human endogenous retroviruses (HERVs). HERV expression following ZNF274 loss induces a double stranded RNA response that reinforces the classical to basal subtype transition. Here, we show ZNF274 is an important epigenetic regulator of cellular plasticity and sensitivity to CDK7 inhibition, presenting a therapeutic liability of PDAC subtype transition that is actionable in the clinic. Pancreatic ductal adenocarcinoma (PDAC) classical and basal subtypes can interconvert. Here, the authors discover that ZNF274 loss drives a classical to basal transition in PDAC via suppression of ZEB1 and HERV-driven interferon signaling, increasing the sensitivity to CDK7 inhibition.