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Mechanistic insights into the clinical Y96D mutation with acquired resistance to AMG510 in the KRASG12C
Zhuang, Haiming1; Fan, Jigang1,2; Li, Mingyu1; Zhang, Hao1; Yang, Xiuyan1,3; Lin, Ligen3; Lu, Shaoyong1,4; Wang, Qing5; Liu, Yaqin4
2022-08-10
Source PublicationFrontiers in Oncology
ISSN2234-943X
Volume12
Abstract

Special oncogenic mutations in the RAS proteins lead to the aberrant activation of RAS and its downstream signaling pathways. AMG510, the first approval drug for KRAS, covalently binds to the mutated cysteine 12 of KRAS protein and has shown promising antitumor activity in clinical trials. Recent studies have reported that the clinically acquired Y96D mutation could severely affect the effectiveness of AMG510. However, the underlying mechanism of the drug-resistance remains unclear. To address this, we performed multiple microsecond molecular dynamics simulations on the KRAS−AMG510 and KRAS−AMG510 complexes at the atomic level. The direct interaction between the residue 96 and AMG510 was impaired owing to the Y96D mutation. Moreover, the mutation yielded higher flexibility and more coupled motion of the switch II and α3-helix, which led to the departing motion of the switch II and α3-helix. The resulting departing motion impaired the interaction between the switch II and α3-helix and subsequently induced the opening and loosening of the AMG510 binding pocket, which further disrupted the interaction between the key residues in the pocket and AMG510 and induced an increased solvent exposure of AMG510. These findings reveal the resistance mechanism of AMG510 to KRAS, which will help to offer guidance for the development of KRAS targeted drugs to overcome acquired resistance.

KeywordAmg510 Drug Resistance G12c Kras Molecular Dynamics Simulations
DOI10.3389/fonc.2022.915512
URLView the original
Indexed BySCIE
Language英語English
WOS Research AreaOncology
WOS SubjectOncology
WOS IDWOS:000844016500001
Scopus ID2-s2.0-85136588923
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Cited Times [WOS]:1   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Affiliation1.Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
2.Zhiyuan Innovative Research Center, Shanghai Jiao Tong University, Shanghai, China
3.State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao
4.Medicinal Chemistry and Bioinformatics Center, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
5.Oncology Department, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China
Recommended Citation
GB/T 7714
Zhuang, Haiming,Fan, Jigang,Li, Mingyu,et al. Mechanistic insights into the clinical Y96D mutation with acquired resistance to AMG510 in the KRASG12C[J]. Frontiers in Oncology,2022,12.
APA Zhuang, Haiming,Fan, Jigang,Li, Mingyu,Zhang, Hao,Yang, Xiuyan,Lin, Ligen,Lu, Shaoyong,Wang, Qing,&Liu, Yaqin.(2022).Mechanistic insights into the clinical Y96D mutation with acquired resistance to AMG510 in the KRASG12C.Frontiers in Oncology,12.
MLA Zhuang, Haiming,et al."Mechanistic insights into the clinical Y96D mutation with acquired resistance to AMG510 in the KRASG12C".Frontiers in Oncology 12(2022).
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