Persister cell phenotypes contribute to poor patient outcomes after neoadjuvant chemotherapy in PDAC (Hipo 015)

Neoadjuvant chemotherapy can improve the survival of patients with borderline and unresectable pancreatic ductal adenocarcinoma (PDAC), however, heterogeneous responses to chemotherapy remain a significant clinical challenge. Here, we performed RNAseq (n=97) and multiplexed immunofluorescence (n=122) on chemo-naïve and post-chemotherapy (post-CTX) resected patient samples (chemoradiotherapy excluded) to define the molecular and cellular impact of neoadjuvant chemotherapy. Transcriptome analysis combined with high resolution mapping of whole tissue sections identified GATA6 (Classical), KRT17 (Basal-like) and Cytochrome P450 3A (CYP3A) co-expressing cells that were preferentially enriched in post-CTX resected samples. The persistence of GATA6Hi and KRT17Hi cells post-CTX was significantly associated with poor survival after mFOLFIRINOX (mFFX), but not gemcitabine. Analysis of organoid models derived from chemo-naïve and post-CTX samples, demonstrated that CYP3A expression is a predictor of chemotherapy response and that CYP3A-expressing drug detoxification pathways can metabolize the prodrug irinotecan, a constituent of mFFX. Taken together, these findings identify CYP3A-expressing drug-resistant cell phenotypes in residual disease that may ultimately inform adjuvant treatment selection.EGA study EGAS00001007143