%0 Journal Article
%T Persister cell phenotypes contribute to poor patient outcomes after neoadjuvant chemotherapy in PDAC.
%A Zhou X
%A An J
%A Kurilov R
%A Brors B
%A Hu K
%A Peccerella T
%A Roessler S
%A Pfütze K
%A Schulz A
%A Wolf S
%A Hohmann N
%A Theile D
%A Sauter M
%A Burhenne J
%A Ei S
%A Heger U
%A Strobel O
%A Barry ST
%A Springfeld C
%A Tjaden C
%A Bergmann F
%A Büchler M
%A Hackert T
%A Fortunato F
%A Neoptolemos JP
%A Bailey P
%J Nat Cancer
%V 4
%N 9
%D 2023 09 7
%M 37679568
%F 23.177
%R 10.1038/s43018-023-00628-6
%X Neoadjuvant chemotherapy can improve the survival of individuals with borderline and unresectable pancreatic ductal adenocarcinoma; however, heterogeneous responses to chemotherapy remain a significant clinical challenge. Here, we performed RNA sequencing (n = 97) and multiplexed immunofluorescence (n = 122) on chemo-naive and postchemotherapy (post-CTX) resected patient samples (chemoradiotherapy excluded) to define the 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) coexpressing 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 (GEM), treatment. Analysis of organoid models derived from chemo-naive 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. These findings identify CYP3A-expressing drug-tolerant cell phenotypes in residual disease that may ultimately inform adjuvant treatment selection.