Abstract A037: DeltaNp63 loss defines resistance to CDK7 inhibitors in basal pancreatic ductal adenocarcinoma

Abstract

Pancreatic Ductal Adenocarcinoma (PDAC) is characterized by two distinct transcriptional subtypes, classical and basal-like. Basal-like PDAC (∼25%) has worse overall survival and is the only class to act as an independent poor prognostic factor. The transcriptional subtypes are also marked by differential chromatin and epigenetic landscapes. Importantly, lineage plasticity exists within the subtypes, facilitating cell state conversion. We recently discovered that basal PDAC is exquisitely sensitive to cyclin dependent 7 kinase inhibitors (CDK7i). This was due in large part to instability of the key integrated stress pathway regulator, ATF4, in basal PDAC, leading to apoptosis. Using aquired CDK7i resistant basal PDAC lines, we discovered, through RNA-seq analysis, that deltaNp63 (ΔNp63) was downregulated leading to an increase in ATF4 and loss of key regulators of basal identify, including cytokeratin 5. Genetic knockdown studies recapitulated what was observed in CDK7i resistant clones in that when we knocked down ΔNp63 in basal lines, we observed an increase in ATF4, decreased translation, increased GATA6 expression and decreased sensitvity to CDK7i. Conversely, when we overexpressed ΔNp63 in classical lines, we observed a drastic decrease in ATF4, increase in puromycin uptake and increased sensitivity to CDK7i. Our results suggest CDK7i resistant clones acquire a more classical phenotype associated with circumvention of CDK7i sensitivity. The plasticity observed through downregulation of squamous-basal transcription factor, ΔNp63, and impact upon the integrated stress response, has the potential of providing innovative therapeutic stratgeies for basal PDAC and informing combination therapy for a future clinical trial.