下调和上调
癌症研究
天冬酰胺
异源双工
生物
成纤维细胞生长因子受体2
分子生物学
化学
DNA
受体
生物化学
成纤维细胞生长因子
基因
氨基酸
作者
Zhenzhen Chu,Baohuan Zhang,Xueping Zhou,Hui Yuan,Chongqing Gao,Lihao Liu,Yang Xiao,Jichun Zhang,Jian Hong,Junjie Liang,Dong Chen,Nan Yao
标识
DOI:10.1016/j.omtn.2023.102047
摘要
Pemigatinib, a pan-FGFR inhibitor, is approved to treat intrahepatic cholangiocarcinoma (ICC) harboring FGFR2 fusion mutations. Improving its targeting of FGFR2 fusions remains an unmet clinical need due to its pan selectivity and resistance. Here, we report a cholesterol-conjugated DNA/RNA heteroduplex oligonucleotide targeting the chimeric site in FGFR2-AHCYL1 (F-A Cho-HDO) that accumulates in ICC through endocytosis of low-density lipoprotein receptor (LDLR), which is highly expressed in both human and murine ICC. F-A Cho-HDO was determined to be a highly specific, sustainable, and well-tolerated agent for inhibiting ICC progression through posttranscriptional suppression of F-A in ICC patient-derived xenograft mouse models. Moreover, we identified an EGFR-orchestrated bypass signaling axis that partially offset the efficacy of F-A Cho-HDO. Mechanistically, EGFR-induced STAT1 upregulation promoted asparagine (Asn) synthesis through direct transcriptional upregulation of asparagine synthetase (ASNS) and dictated cell survival by preventing p53-dependent cell cycle arrest. Asn restriction with ASNase or ASNS inhibitors reduced the intracellular Asn, thereby reactivating p53 and sensitizing ICC to F-A Cho-HDO. Our findings highlight the application of genetic engineering therapies in ICC harboring FGFR2 fusions and reveal an axis of adaptation to FGFR2 inhibition that presents a rationale for the clinical evaluation of a strategy combining FGFR2 inhibitors with Asn depletion.
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