Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the US. This poor prognosis is related to the complex tumor microenvironment and tumor heterogeneity that drives resistance to chemotherapy. Here the heterogeneity of the stromal, immune, and malignant epithelial cell populations enables signaling and metabolic crosstalk mechanisms that drive immune suppression and resistance to therapy. Recently, our group unveiled that multiple distinct metabolic subclasses of cancer cells coexist within individual PDAC tumors. Among these, two PDAC clonal populations can engage in metabolic symbiosis that supports mitochondrial metabolism. One subtype has a constitutively high integrated stress response (ISR), enabling resistance to mitochondrial inhibitors. Further, these cells release asparagine that supports the mitochondrial metabolism of the other subtype that are more sensitive to mitochondrial inhibition. Given these observations, we are developing approaches to disrupt this metabolic symbiosis. Clonal PDAC cells with constitutively active ISR exhibit increased sensitivity to inhibition of the redox activity of Redox factor 1/Apurinic-apyrimidinic endonuclease 1 (Ref-1). Importantly, this can be leveraged to disrupt the support of the mitochondrial metabolism of clonal symbiotic pairs. Moreover, polyclonal PDAC cell lines representative of the heterogeneity seen in PDAC patients show a highly synergistic response to the combination of Ref-1 redox inhibitors with mitochondrial inhibitors. These data suggest this treatment combination will be synergistic in polyclonal tumors that exist in most PDAC patients. Overall, these data have the potential to lead to new avenues to directly target heterogenous populations of cancer cells to treat pancreatic cancer- an urgent clinical need. Citation Format: Taryn Morningstar, Cecily Anaraki, Lorenzo Scipioni, Giulia Tedeschi, Michelle Digman, Aimee Edinger, Claus Jorgensen, Melissa Fishel, Christopher J Halbrook. Targeting metabolic heterogeneity in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C045.