Abstract 6803: Targeting mitochondrial complex I overcomes adaptive response to chemotherapy in advanced pancreatic cancer

Abstract Chemotherapy remains the mainstay for treatment in patients with advanced pancreatic ductal adenocarcinoma (PDAC), but acquired therapeutic resistance remains a major challenge to sustaining responses. Here, we leveraged a high complexity barcoding technology to identify and isolate clonal lineages showing different sensitivity to chemotherapy in vivo in PDAC. Using transcriptomic profiling of chemotherapy sensitive and non-sensitive clonal lineages, we developed a prognostic gene signature named as chemo-type that enables the stratification of patients survival and predicts their response to chemotherapy in two independent datasets including n=301 human PDAC patients. We applied the chemo-type signature to stratify n=36 patient-derived xenograft models of PDAC based on their sensitivity to chemotherapy and to investigate vulnerabilities. We found that Oxidative Phosphorylation (OxPhos) is an adaptive stress response to chemotherapy in a subset of PDAC xenograft models which can potentially benefit from OxPhos inhibition and can be predicted by the chemo-type signature. We demonstrated that a combinatorial approach targeting OxPhos in addition with chemotherapy in PDAC xenograft models eradicates chemotherapy-resistant clones, thereby suppressing tumor relapse and prolonging survival, using a new inhibitor of the mitochondrial complex I named as IM156, which is currently under evaluation in a phase Ib clinical trial for patients with advanced pancreatic cancer. Citation Format: Sergio Attanasio, Francesca Citron, Rutvi Shah, Fen Saj, Zhaoliang Liu, I-Lin Ho, Er-Yen Yen, Charles A. Dyke, Hyuk Jean Kwon, Luca Cecchetto, Ziheng Chen, Elisabetta Granato, Sara Sanjay Sainani, Sara Loponte, Yanshuo Chu, Melinda Seoung, Luigi Perelli, Shan Jiang, Prasanta Dutta, Pratip Bhattacharya, Huamin Wang, Linghua Wang, Michael Paul Kim, Giannicola Genovese, Costas Andreas Lyssiotis, David G. Menter, Giulio F. Draetta, Scott Kopetz, Anirban Maitra, Shubham Pant, Andrea Viale. Targeting mitochondrial complex I overcomes adaptive response to chemotherapy in advanced pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6803.