Inhibition of ERAD synergizes with FTS to eradicate pancreatic cancer cells

BMC Cancer

Nancy G. Azizian¹  Yuanhui Liu¹  Yulin Li¹  Rong Du²  Delaney K. Sullivan³ 

[1] Center for Immunotherapy Research, Houston Methodist Research Institute, 77030, Houston, TX, USA;Department of Medicine, Weill Cornell Medical College, 10065, New York, NY, USA;Center for Immunotherapy Research, Houston Methodist Research Institute, 77030, Houston, TX, USA;Department of Medicine, Weill Cornell Medical College, 10065, New York, NY, USA;Department of Neurosurgery, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China;UCLA-Caltech Medical Scientist Training Program, David Geffen School of Medicine, University of California, 90095, Los Angeles, CA, USA;

关键词: Pancreatic ductal adenocarcinoma (PDAC);    Clusters of regularly interspaced short palindromic repeats (CRISPR);    Farnesyl thiosalicylic acid (FTS);    Salirasib;    Endoplasmic reticulum-associated protein degradation (ERAD);    Unfolded protein response (UPR);   

DOI  :  10.1186/s12885-021-07967-6

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY