Inhibition of ERAD synergizes with FTS to eradicate pancreatic cancer cells

• Published in: BMC cancer Vol. 21; no. 1; p. 237
• Main Authors: Du, Rong, Sullivan, Delaney K, Azizian, Nancy G, Liu, Yuanhui, Li, Yulin
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 06-03-2021; BioMed Central; BMC
• Subjects: Adenocarcinoma; Animals; Antimitotic agents; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Binding sites; Cancer; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - pathology; Care and treatment; Cell Line, Tumor; Cell membranes; Chemical properties; Clusters of regularly interspaced short palindromic repeats (CRISPR); CRISPR; CRISPR-Cas Systems - genetics; Data analysis; Drug Screening Assays, Antitumor; Endoplasmic reticulum; Endoplasmic Reticulum-Associated Degradation - drug effects; Endoplasmic Reticulum-Associated Degradation - genetics; Endoplasmic reticulum-associated protein degradation (ERAD); Farnesol - analogs & derivatives; Farnesol - pharmacology; Farnesol - therapeutic use; Farnesyl thiosalicylic acid (FTS); Gene expression; Gene Knockout Techniques; Genetic aspects; Genomes; Health aspects; Humans; Hydrazones - pharmacology; Hydrazones - therapeutic use; Hydroxyurea - analogs & derivatives; Hydroxyurea - pharmacology; Hydroxyurea - therapeutic use; Lethality; Localization; Mice; Mutation; Oncology, Experimental; Pancreatic cancer; Pancreatic ductal adenocarcinoma (PDAC); Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - pathology; Protein folding; Proteins; Proteins - genetics; Proteolysis; Ras protein; Salicylates - pharmacology; Salicylates - therapeutic use; Salicylic acid; Salirasib; Signal transduction; Synergism; Synthetic Lethal Mutations; Thiosalicylic acid; Ubiquitin-Protein Ligases - genetics; Unfolded protein response (UPR); Unfolded Protein Response - drug effects; United States; Clusters of regularly interspaced short palindromic repeats (CRISPR); Endoplasmic reticulum-associated protein degradation (ERAD); Pancreatic ductal adenocarcinoma (PDAC); Salirasib; Farnesyl thiosalicylic acid (FTS); Unfolded protein response (UPR)
• ISSN: 1471-2407; 1471-2407
• DOI: 10.1186/s12885-021-07967-6

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.
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.
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.
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.