A DNA/RNA heteroduplex oligonucleotide coupling asparagine depletion restricts FGFR2 fusion-driven intrahepatic cholangiocarcinoma
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 heterodu...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-12-01
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| Series: | Molecular Therapy: Nucleic Acids |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253123002652 |
| _version_ | 1797655109242454016 |
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| author | Zhenzhen Chu Baohuan Zhang Xuxuan Zhou Hui Yuan Chongqing Gao Lihao Liu Yang Xiao Jichun Zhang Jian Hong Junjie Liang Dong Chen Nan Yao |
| author_facet | Zhenzhen Chu Baohuan Zhang Xuxuan Zhou Hui Yuan Chongqing Gao Lihao Liu Yang Xiao Jichun Zhang Jian Hong Junjie Liang Dong Chen Nan Yao |
| author_sort | Zhenzhen Chu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T17:09:23Z |
| format | Article |
| id | doaj.art-7507306281de4ec691ec8fdaab5a1821 |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-03-11T17:09:23Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-7507306281de4ec691ec8fdaab5a18212023-10-20T06:39:14ZengElsevierMolecular Therapy: Nucleic Acids2162-25312023-12-0134102047A DNA/RNA heteroduplex oligonucleotide coupling asparagine depletion restricts FGFR2 fusion-driven intrahepatic cholangiocarcinomaZhenzhen Chu0Baohuan Zhang1Xuxuan Zhou2Hui Yuan3Chongqing Gao4Lihao Liu5Yang Xiao6Jichun Zhang7Jian Hong8Junjie Liang9Dong Chen10Nan Yao11Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, ChinaMorphology Experimental Teaching Center, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, ChinaDepartment of Pathophysiology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, ChinaDepartment of Gastroenterology, Huizhou Municipal Central Hospital, Huizhou, Guangdong 516001, ChinaDepartment of Pathophysiology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, ChinaSchool of Medicine, Jinan University, Guangzhou, Guangdong 510632, ChinaDepartment of Hepatobiliary Surgery, the First Affiliated Hospital, Jinan University, Guangzhou, Guangdong 510632, ChinaDepartment of Physiology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, ChinaDepartment of Pathophysiology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China; Department of Hepatobiliary Surgery, the First Affiliated Hospital, Jinan University, Guangzhou, Guangdong 510632, ChinaDepartment of Hepatobiliary Surgery, the First Affiliated Hospital, Jinan University, Guangzhou, Guangdong 510632, China; Corresponding author: Junjie Liang, Department of Hepatobiliary Surgery, the First Affiliated Hospital, Jinan University, Guangzhou, Guangdong 510632, China.Department of Pancreato-Biliary Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China; Corresponding author: Dong Chen, Department of Pancreato-Biliary Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China; Corresponding author: Nan Yao, Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China.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.http://www.sciencedirect.com/science/article/pii/S2162253123002652MT: Oligonucleotides: Therapies and Applicationsintrahepatic cholangiocarcinomaFGFR2 fusion mutationsnucleic acid drugstargeted therapycombination therapy |
| spellingShingle | Zhenzhen Chu Baohuan Zhang Xuxuan Zhou Hui Yuan Chongqing Gao Lihao Liu Yang Xiao Jichun Zhang Jian Hong Junjie Liang Dong Chen Nan Yao A DNA/RNA heteroduplex oligonucleotide coupling asparagine depletion restricts FGFR2 fusion-driven intrahepatic cholangiocarcinoma Molecular Therapy: Nucleic Acids MT: Oligonucleotides: Therapies and Applications intrahepatic cholangiocarcinoma FGFR2 fusion mutations nucleic acid drugs targeted therapy combination therapy |
| title | A DNA/RNA heteroduplex oligonucleotide coupling asparagine depletion restricts FGFR2 fusion-driven intrahepatic cholangiocarcinoma |
| title_full | A DNA/RNA heteroduplex oligonucleotide coupling asparagine depletion restricts FGFR2 fusion-driven intrahepatic cholangiocarcinoma |
| title_fullStr | A DNA/RNA heteroduplex oligonucleotide coupling asparagine depletion restricts FGFR2 fusion-driven intrahepatic cholangiocarcinoma |
| title_full_unstemmed | A DNA/RNA heteroduplex oligonucleotide coupling asparagine depletion restricts FGFR2 fusion-driven intrahepatic cholangiocarcinoma |
| title_short | A DNA/RNA heteroduplex oligonucleotide coupling asparagine depletion restricts FGFR2 fusion-driven intrahepatic cholangiocarcinoma |
| title_sort | dna rna heteroduplex oligonucleotide coupling asparagine depletion restricts fgfr2 fusion driven intrahepatic cholangiocarcinoma |
| topic | MT: Oligonucleotides: Therapies and Applications intrahepatic cholangiocarcinoma FGFR2 fusion mutations nucleic acid drugs targeted therapy combination therapy |
| url | http://www.sciencedirect.com/science/article/pii/S2162253123002652 |
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