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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-naïve 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 Schäfer, Carlo Maurer, Sebastian Lange, Felix Orben, Raquel Bernad, Felix Harder, Matthias Eiber, Rupert Öllinger, Melissa Schlitter, Wilko Weichert, Veit Phillip, Christoph Schlag, Roland Schmid, Rickmer Braren, Bo Kong, Ekin Demir, Helmut Friess, Roland Rad, Dieter Saur, Günter 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.

Despite recent improvements in treatment regimen such as combination chemotherapies, pancreatic ductal adenocarcinoma still carries a dismal prognosis with an overall survival rate of 9%. The oncogenic transcription factor MYC is amplified in about 12% of all PDAC, which is connected to a worse survival. It is clear that hyperactivation of MYC generates dependencies that can be exploited therapeutically. Therefore, the aim of the study was to find and to target MYC-associated dependencies. Human PDAC gene expression data sets were analyzed. Moreover, analysis of the SUMO pathway in large cohort of PDAC was performed by IHC. Furthermore, a novel, pharmacological SUMO inhibitor was used and characterized by using human and murine 2D-, organoid-, and in vivo-models of PDAC. In addition, this connection was also verified by the genetically modified human and murine models. Large-scale gene expression datasets of human PDACs analysis revealed a connection of MYC to the SUMOylation machinery in PDAC. Moreover, results were also corroborated by the hyperactivation of SUMO pathway in a large patient cohort which characterized a PDAC subtype with a dismal prognosis. We furthermore corroborated these results by using the novel SUMO inhibitor ML093 by in vitro studies that hyperactivation of MYC is connected to an increased sensitivity to pharmacological SUMO inhibition. In conclusion, SUMO inhibitor-based therapies should be further developed for an aggressive PDAC subtype. Citation Format: Zonera Hassan, Alex Biederstädt, Christian Schneeweis, Markus Schick, Nilsson Jonas, Mathias Wirth, Andrea Coluccio, Felix Orben, Katja Steiger, Jolanta Slawska, Steve Langston, Dieter Saur, Roland Rad, Maximilian Reichert, Guenter Schneider, Ulrich Keller. Interaction of MYC and SUMOylation machinery in an aggressive pancreatic cancer subtype [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1793.