2. Academic Validation
  3. Leveraging autophagy and pyrimidine metabolism to target pancreatic cancer

Leveraging autophagy and pyrimidine metabolism to target pancreatic cancer

  • bioRxiv. 2025 Jun 5:2025.05.29.656904. doi: 10.1101/2025.05.29.656904.
Suzanne Dufresne 1,  Ramya S Kuna 1,  Kristiana Wong 1 2,  Anvita Komarla 1 3,  Angelica Rock 1 2,  Joel Rosada-Encarnación 1,  Celina Shen 1 2,  Payel Mondal 1,  Louis R Parham 1,  Fabiana Izidro Layng 4,  Kristina L Peck 5,  Alexandra Fowler 5,  Andrew M Lowy 6,  Dannielle Engle 5,  Herve Tiriac 6,  Reuben Shaw 1,  Nicholas Cosford 4,  Christian Metallo 1,  Christina Towers 1
Affiliations

Affiliations

  • 1 Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
  • 2 Division of Biological Sciences, University of California San Diego, La Jolla, CA 92037, USA.
  • 3 Department of Bioengineering, University of California San Diego, La Jolla, CA 92037, USA.
  • 4 Cancer Molecular Therapeutics Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
  • 5 Regulatory Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
  • 6 Department of Surgery, Division of Surgical Oncology, Moores Cancer Center, University of California San Diego, La Jolla, CA 92037, USA.
PMID: 40501952 DOI: 10.1101/2025.05.29.656904
Abstract

Autophagy inhibitors are promising compounds to treat pancreatic ductal adenocarcinoma (PDA) but their efficacy in patients is unclear, highlighting a need to understand mechanisms of resistance. We used a novel approach to uncover metabolic adaptations that bypass Autophagy inhibition. Utilizing PDA cells with acquired resistance to different Autophagy inhibitors, we found that severe Autophagy depletion induces metabolic rewiring to sustain TCA intermediates and nucleotides for biosynthesis. Long-term Autophagy inhibition results in altered pyruvate metabolism likely regulated by lower pyrimidine pools. Cells adapting to loss of Autophagy preferentially salvage pyrimidines to replenish these pools instead of synthesizing them de novo. Exploiting this metabolic vulnerability, we found that acquired resistance to Autophagy inhibition promotes increased salvage and therefore sensitivity to pyrimidine analogues, including gemcitabine and trifluridine/tipiracil leading to combinatory effects with Autophagy inhibitors and pyrimidine analogs. These studies provide mechanistic insight defining how Autophagy inhibition can be leveraged to treat pancreatic Cancer.

Keywords

Autophagy; ULK1/2; drug resistance; gemcitabine; hydroxychloroquine; lysosomes; nucleotides; pancreatic cancer; pyrimidine metabolism; pyruvate metabolism.

Figures
Products