Abstract
BackgroundPancreatic 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.MethodsTo 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.ResultsIn 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.ConclusionOur 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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC), one of the most lethal cancers, is driven by oncogenic KRAS mutations
Farnesyl thiosalicylic acid (FTS) pool was treated with the drug for 12 days, while the control pool was maintained in culture
We demonstrated that inhibition of endoplasmic reticulum-associated protein degradation (ERAD), a downstream cellular process triggered by unfolded protein response (UPR), enhanced FTS efficacy, suggesting that FTS likely induces UPR in the KRAS-driven PDAC tumor cells
Summary
Pancreatic ductal adenocarcinoma (PDAC), one of the most lethal cancers, is driven by oncogenic KRAS mutations. Farnesyl thiosalicylic acid (FTS), known as salirasib, is a RAS inhibitor that selectively dislodges active RAS proteins from cell membrane, inhibiting downstream signaling. KRAS mutations have been identified as the oncogenic driver in PDAC [2]. RAS is a membrane bound GTPase that functions as a molecular switch, cycling between active GTP-bound state facilitated by guanine nucleotide exchange factors, Given its critical function as an oncogenic driver, extensive efforts have been devoted to the development of specific RAS inhibitors [6,7,8]. The lack of binding sites for small chemical inhibitors on the RAS protein surface has hindered the efforts to directly target RAS. In recent years, exciting progresses have been made in directly targeting the rare KRASG12C mutant [10,11,12,13,14], but not the more prevalent mutations, such as G12D, G12V, and G12R
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