JC-010a, a novel selective SHP2 allosteric inhibitor, overcomes RTK/non-RTK-mediated drug resistance in multiple oncogene-addicted cancers | |
Lu, Xuxiu2,3; Yu, Rilei2,3; Li, Zhen3; Yang, Mengke3; Dai, Jiajia1; Liu, Ming2,3 | |
刊名 | CANCER LETTERS |
2024-02-01 | |
卷号 | 582页码:15 |
关键词 | Acquired resistance Cancer NSCLC JC-010a SHP2 |
ISSN号 | 0304-3835 |
DOI | 10.1016/j.canlet.2023.216517 |
通讯作者 | Liu, Ming(lmouc@ouc.edu.cn) |
英文摘要 | 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. |
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关键词 | PROTEIN-TYROSINE PHOSPHATASES ; BCR-ABL ; MECHANISMS ; THERAPY |
WOS研究方向 | Oncology |
语种 | 英语 |
出版者 | ELSEVIER IRELAND LTD |
WOS记录号 | WOS:001156741000001 |
内容类型 | 期刊论文 |
源URL | [http://ir.qdio.ac.cn/handle/337002/184490] |
专题 | 海洋研究所_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.Chinese Acad Sci, Inst Oceanol, Key Lab Marine Ecol & Environm Sci, Qingdao 266071, Peoples R China 2.Qingdao Natl Lab Marine Sci & Technol, Lab Marine Drugs & Bioprod, Qingdao 266237, Peoples R China 3.Ocean Univ China, Sch Med & Pharm, Key Lab Marine Drugs, Minist Educ, Qingdao 266003, 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. |
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