Center for Immunotherapy Research, Houston Methodist Research Institute, Houston, TX, 77030, USA.
Department of Medicine, Weill Cornell Medical College, New York, NY, 10065, USA.
BMC Cancer. 2021 Mar 6;21(1):237. 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.
胰腺导管腺癌（PDAC）是最致命的癌症之一，其发生由致癌性 KRAS 突变驱动。法尼酰硫代水杨酸（FTS），又称 salirasib，是一种 RAS 抑制剂，可选择性地将活性 RAS 蛋白从细胞膜上置换下来，抑制下游信号转导。尽管 FTS 具有良好的耐受性，但在 PDAC 患者中其治疗效果有限。
为了提高 FTS 在 PDAC 中的疗效，我们进行了全基因组 CRISPR 合成致死性筛选，以确定与 FTS 治疗协同作用的遗传靶标。在顶级候选物中，鉴定出内质网相关蛋白降解（ERAD）途径中的多个基因。使用药物和遗传方法进一步研究了 ERAD 抑制在增强 FTS 治疗疗效中的作用。
在鼠和人 PDAC 细胞中，FTS 诱导未折叠蛋白反应（UPR），在用 ERAD 的化学抑制剂 Eeyarestatin I（EerI）处理时进一步增强。FTS 和 EerI 的联合治疗显著上调了 UPR 标志物基因的表达，并诱导了胰腺癌细胞凋亡。此外，基于 CRISPR 的关键 ERAD 成分 HRD1 和 SEL1L 的遗传消融使 PDAC 细胞对 FTS 治疗敏感。
我们的研究揭示了 ERAD 在 FTS 治疗反应中的关键作用，并指出了 UPR 的调节作为提高 FTS 在 PDAC 治疗中的疗效的新方法。
