Abstract PO-070: Longitudinal precision oncology platform to identify chemotherapy-induced vulnerabilities in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) remains a devastating disease with poor survival rates as almost all patients develop resistance towards chemotherapy and molecular-informed targeted therapies are reserved to a few. Here, we aim to establish a longitudinal precision oncology platform with a multi-dimensional characterization of PDAC biopsies including genomic, transcriptomic as well as functional analyses to identify and exploit treatment-induced vulnerabilities. In order to investigate adaptive processes of tumors under treatment we aimed to generate PDAC patient-derived organoids (PDOs) and 2D cell lines before and after chemotherapy. Therefore, we enrolled a patient with borderline resectable PDAC who received neoadjuvant FOLFIRINOX. Endoscopic fine needle (pre-FFX) and surgical biopsies (post-FFX) were used to generate PDOs and 2D cells. Whole exome sequencing (WES) and RNA sequencing data of the pre-FFX and post-FFX organoids were compared in order to evaluate the genetic landscape and PDAC subtypes. 2D cells were subjected to an unbiased automated drug screening of 415 compounds to investigate FFX-induced vulnerabilities. Top targets were validated manually in the 2D cells and organoids. Although transcriptional subtyping classified both PDOs as classical PDAC, gene set enrichment analysis (GSEA) revealed a reduced pathway activation linked to the basal-like phenotype such as KRAS signaling in the post-FFX organoids. WES did not show major differences in the genetic landscape of the tumor pre- and post-FFX induction suggesting a plasticity process rather than a clonal selection during chemotherapy. Importantly, post-FFX cells exhibited an increased sensitivity in the unbiased drug screening towards MEK and EGFR inhibition compared to pre-FFX cells. 2D cells and organoids were treated with different MEK inhibitors (MEKi) for validation and post-FFX cells showed a highly increased response compared to the treatment-naive cells, as well. Interestingly, when placed into the context of a panel of 15 primary PDAC cell lines the pre-FFX cells cluster with highly MEKi resistant PDAC cells whereas post-FFX cells belong to the most sensitive cell lines. In sum, integrating functional layers into personalized medicine allowed us to identify chemotherapy-induced vulnerabilities as potent targeted therapy options in PDAC. Thus, this longitudinal precision oncology platform harbors a unique opportunity to understand adaptive processes in tumor evolution and/or treatment-imposed pressure in PDAC patients. Citation Format: Katja Peschke, Hannah Jakubowski, Arlett Schafer, Carlo Maurer, Sebastian Lange, Felix Orben, Raquel Bernad, Felix Harder, Matthias Eiber, Rupert Ollinger, Melissa Schlitter, Wilko Weichert, Veit Phillip, Christoph Schlag, Roland Schmid, Rickmer Braren, Bo Kong, Ekin Demir, Helmut Friess, Roland Rad, Dieter Saur, Gunter Schneider, Maximilian Reichert. Longitudinal precision oncology platform to identify chemotherapy-induced vulnerabilities in pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-070.