Inhibition of ERAD synergizes with FTS to eradicate pancreatic cancer cells

Rong Du, Delaney K. Sullivan, Nancy G. Azizian, Yuanhui Liu, Yulin Li

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


Background: Pancreatic ductal adenocarcinoma (PDAC), one of the most lethal cancers, is driven by oncogenic KRAS mutations. Farnesyl thiosalicylic acid (FTS), also known as salirasib, is a RAS inhibitor that selectively dislodges active RAS proteins from cell membrane, inhibiting downstream signaling. FTS has demonstrated limited therapeutic efficacy in PDAC patients despite being well tolerated. Methods: To improve the efficacy of FTS in PDAC, we performed a genome-wide CRISPR synthetic lethality screen to identify genetic targets that synergize with FTS treatment. Among the top candidates, multiple genes in the endoplasmic reticulum-associated protein degradation (ERAD) pathway were identified. The role of ERAD inhibition in enhancing the therapeutic efficacy of FTS was further investigated in pancreatic cancer cells using pharmaceutical and genetic approaches. Results: In murine and human PDAC cells, FTS induced unfolded protein response (UPR), which was further augmented upon treatment with a chemical inhibitor of ERAD, Eeyarestatin I (EerI). Combined treatment with FTS and EerI significantly upregulated the expression of UPR marker genes and induced apoptosis in pancreatic cancer cells. Furthermore, CRISPR-based genetic ablation of the key ERAD components, HRD1 and SEL1L, sensitized PDAC cells to FTS treatment. Conclusion: Our study reveals a critical role for ERAD in therapeutic response of FTS and points to the modulation of UPR as a novel approach to improve the efficacy of FTS in PDAC treatment.

Original languageEnglish (US)
Article number237
Pages (from-to)237
Number of pages13
JournalBMC Cancer
Issue number1
StatePublished - Mar 6 2021


  • Clusters of regularly interspaced short palindromic repeats (CRISPR)
  • Endoplasmic reticulum-associated protein degradation (ERAD)
  • Farnesyl thiosalicylic acid (FTS)
  • Pancreatic ductal adenocarcinoma (PDAC)
  • Salirasib
  • Unfolded protein response (UPR)
  • Endoplasmic Reticulum-Associated Degradation/drug effects
  • Hydrazones/pharmacology
  • Humans
  • Unfolded Protein Response/drug effects
  • Synthetic Lethal Mutations
  • Proteins/genetics
  • Antineoplastic Combined Chemotherapy Protocols/pharmacology
  • CRISPR-Cas Systems/genetics
  • Pancreatic Neoplasms/drug therapy
  • Salicylates/pharmacology
  • Apoptosis/drug effects
  • Carcinoma, Pancreatic Ductal/drug therapy
  • Gene Knockout Techniques
  • Animals
  • Farnesol/analogs & derivatives
  • Cell Line, Tumor
  • Hydroxyurea/analogs & derivatives
  • Mice
  • Ubiquitin-Protein Ligases/genetics
  • Drug Screening Assays, Antitumor

ASJC Scopus subject areas

  • Oncology
  • Genetics
  • Cancer Research


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