Abstract A010: Persister cell phenotypes contribute to poor patient outcomes after neoadjuvant chemotherapy in PDAC

Abstract

The impact of neoadjuvant chemotherapy on tumor cells is largely unknown with resistance to therapy remaining a significant challenge. We analyzed 171 chemo-naïve and post-chemotherapy resected patient samples (chemoradiotherapy excluded) using RNAseq and multiplexed immunofluorescence. Neoadjuvant chemotherapy enriched for distinct neoplastic persister phenotypes expressing Classical and Basal-like biomarkers GATA6 and KRT17. The enrichment of GATA6HiClassical-like and KRT17Hi Basal-like cells in post-chemotherapy patient samples was associated with poor survival after mFOLFIRINOX, but not gemcitabine. CYP3A subfamily enzymes (CYP3A4 and CYP3A5) were expressed in GATA6Hi and KRT17Hi persister cells and can degrade mFOLFIRINOX constituent irinotecan. Taken together these data support a model in which pre-existing subpopulations of GATA6Hi (Classical) and/or KRT17Hi (Basal) neoplastic cells emerge after mFOLFIRINOX treatment by expressing CYP3A. The identification of CYP3A-enabled persister cell phenotypes is an important step in the design of effective therapies to overcome drug-tolerance and prevent recurrence after neoadjuvant therapy. Citation Format: Xu Zhou, Roma Kurilov, John P. Neoptolemos, Benedikt Brors, Kai Hu, Teresa Peccerella, Jing-Yu An, Stephanie Roessler, Katrin Pfütze, Angela Schulz, Stephan Wolf, Nicolas Hohmann, Ulrike Heger, Oliver Strobel, Simon T Barry, Christoph Springfeld, Christine Tjaden, Frank Bergmann, Markus Büchler, Thilo Hackert, Franco Fortunato, Peter Bailey. Persister cell phenotypes contribute to poor patient outcomes after neoadjuvant chemotherapy in PDAC [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A010.

Neoadjuvant chemo‐ or chemo‐radiation‐therapy of pancreatic ductal adenocarcinoma differentially shift ECM composition, complement activation, energy metabolism and ribosomal proteins of the residual tumor mass

“…With the exception of COL12A1, collagen expression remained unchanged between NCRT and treatment‐naïve PDAC. In contrast with these findings, a RNA‐Seq profiling study encompassed enriched ECM organization and collagen formation in NCT as compared to treatment‐naïve PDAC 38 . A second gene expression study reported increased collagen transcription in NCRT‐treated samples as compared to biopsies taken before the intended neoadjuvant therapy 39 .…”

“…In contrast with these findings, a RNA-Seq profiling study encompassed enriched ECM organization and collagen formation in NCT as compared to treatment-naïve PDAC. 38 A second gene expression study reported increased collagen transcription in NCRT-treated samples as compared to biopsies taken before the intended neoadjuvant therapy. 39 Taken together, this is an area of ongoing research, especially since a fibrotic ECM rich in collagens is a hallmark of PDAC, promoting tumor progression and chemoresistance.…”

Refining the Treatment of Pancreatic Cancer From Big Data to Improved Individual Survival

“… 110 New evidence from our laboratory suggests that drug tolerant cells or “persisters” can emerge from a pre-existing subpopulation of neoplastic cells following neoadjuvant chemotherapy ( Figure 4 ). 111 These persister-like cells adapt to chemotherapy by upregulating CYP3A5 and other co-expressed drug-metabolizing genes, which metabolize the prodrug irinotecan a constituent of FOLFIRINOX into nonactive forms ( Figure 5 ). While persister cells are commonly associated with bacterial infections, there is growing evidence that analogous cell populations (alternatively referred to as “cancer stem cells” or “tumor-initiating cells”) may exist in tumors.…”

“… 112–114 Chemotherapy can induce drug-tolerant persister cell phenotypes from distinct tumor cell lineages leading to tumor relapse. 11 , 83 , 111 , 115 The acquired drug-tolerant persister cells do not in the main involve mutations that confer therapy resistance, suggesting that alternative mechanisms, including phenotypic plasticity driven by stromal interactions, may be involved. 116 Both chemotherapy using FOLFIRINOX and chemoradiotherapy can induce a transformation to a predominant Basal-like subtype from a Classical-like subtype to associated with greater chemoresistance and reduced patient survival.…”

“… 116 Both chemotherapy using FOLFIRINOX and chemoradiotherapy can induce a transformation to a predominant Basal-like subtype from a Classical-like subtype to associated with greater chemoresistance and reduced patient survival. 75 , 76 , 111 , 117 Platinum therapy after adjuvant or first-line treatment results in recurrent disease associated an increased mutational burden notably neurofibromin (NF1), AKT1, PIK3CA, and serine/threonine kinase 11 (STK11), activating MAPK/ERK and PI3K-AKT signaling, and develops from a synchronous or metachronous primaries (monophyletic and polyphyletic origins). 118 Pancreatic cancer has relatively few neo-antigenic targets, and is embedded in an immunosuppressive cold TME, which hinders intratumoral CD8 + T-cell infiltration and activation rendering single agent immunotherapies with immune checkpoint inhibitors mostly ineffective.…”