JC-010a, a novel selective SHP2 allosteric inhibitor, overcomes RTK/non-RTK-mediated drug resistance in multiple oncogene-addicted cancers

doi:10.1016/j.canlet.2023.216517

	JC-010a, a novel selective SHP2 allosteric inhibitor, overcomes RTK/non-RTK-mediated drug resistance in multiple oncogene-addicted cancers
	Lu, Xuxiu 1,2; Yu, Rilei 1,2; Li, Zhen 1; Yang, Mengke 1; Dai, Jiajia 3; Liu, Ming 1,2
	2024-02-01
发表期刊	CANCER LETTERS
ISSN	0304-3835
卷号	582 页码:15
通讯作者	Liu, Ming(lmouc@ouc.edu.cn)
摘要	Src homology 2 domain-containing phosphatase (SHP2) is a non-receptor protein phosphatase that transduces signals from upstream receptor tyrosine kinases (RTKs)/non-RTKs to Ras/MAPK pathway. Accumulating studies indicated that SHP2 is a critical mediator of resistance to current targeted therapies in multiple cancers. Here, we reported a novel SHP2 allosteric inhibitor JC-010a, which was highly selective to SHP2 and bound at the "tunnel" allosteric site of SHP2. The effect of JC-010a on combating RTK/non-RTK or MAPK inhibitors-induced acquired resistance was explored. Our study demonstrated that JC-010a monotherapy significantly inhibited the proliferation of cancer cells with different oncogenic drivers via inhibiting signaling through SHP2. Importantly, JC-010a abolished acquired resistance induced by targeted therapies: in KRAS-mutant cancers, JC-010a abrogated selumetinib-induced adaptive resistance mediated by RTK/SHP2; in BCR-ABL-driven leukemia cells, we demonstrated JC-010a inhibited BCR-ABL T315I mutation-mediated imatinib resistance and proposed a novel mechanism of JC-010a involving the disrupted co-interaction of SHP2, BCR-ABL, and Hsp90; in non-small cell lung cancer (NSCLC) cells, JC-010a inhibited both EGFR T790M/C797S mutation and alternate RTK-driven resistance to gefitinib or osimertinib; importantly, we first proposed a novel potential therapeutic strategy for RET-rearranged cancer, we confirmed that JC-010a monotherapy inhibited cell resistance to BLU-667, and JC-010a/BLU-667 combination prolonged anticancer response both in vivo and in vitro cancer models by inhibiting the alternate MET activation-induced RAS/MAPK reactivation, thereby promoting cancer cell apoptosis. These findings suggested that JC-010a was a novel selective SHP2 allosteric inhibitor, and combing JC-010a with current targeted therapy agents provided a promising therapeutic approach for clinical resistant cancers.
关键词	Acquired resistance Cancer NSCLC JC-010a SHP2
DOI	10.1016/j.canlet.2023.216517
收录类别	SCI
语种	英语
资助项目	Government Guidance Funds for Local Scientific and Technological Development China ; Qingdao Key Technology Research and Industrialization Demonstration[23-1-4-xxgg-13-nsh] ; Qingdao Science and Technology Development Plan
WOS研究方向	Oncology
WOS类目	Oncology
WOS记录号	WOS:001156741000001
出版者	ELSEVIER IRELAND LTD
WOS关键词	PROTEIN-TYROSINE PHOSPHATASES ; BCR-ABL ; MECHANISMS ; THERAPY
引用统计
文献类型	期刊论文
条目标识符	http://ir.qdio.ac.cn/handle/337002/184491
专题	海洋生态与环境科学重点实验室
通讯作者	Liu, Ming
作者单位	1.Ocean Univ China, Sch Med & Pharm, Key Lab Marine Drugs, Minist Educ, Qingdao 266003, Peoples R China 2.Qingdao Natl Lab Marine Sci & Technol, Lab Marine Drugs & Bioprod, Qingdao 266237, Peoples R China 3.Chinese Acad Sci, Inst Oceanol, Key Lab Marine Ecol & Environm Sci, Qingdao 266071, Peoples R China
推荐引用方式 GB/T 7714	Lu, Xuxiu,Yu, Rilei,Li, Zhen,et al. JC-010a, a novel selective SHP2 allosteric inhibitor, overcomes RTK/non-RTK-mediated drug resistance in multiple oncogene-addicted cancers[J]. CANCER LETTERS,2024,582:15.
APA	Lu, Xuxiu,Yu, Rilei,Li, Zhen,Yang, Mengke,Dai, Jiajia,&Liu, Ming.(2024).JC-010a, a novel selective SHP2 allosteric inhibitor, overcomes RTK/non-RTK-mediated drug resistance in multiple oncogene-addicted cancers.CANCER LETTERS,582,15.
MLA	Lu, Xuxiu,et al."JC-010a, a novel selective SHP2 allosteric inhibitor, overcomes RTK/non-RTK-mediated drug resistance in multiple oncogene-addicted cancers".CANCER LETTERS 582(2024):15.