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Targeted Degradation of SOS1 Exhibits Potent Anticancer Activity and Overcomes Resistance in KRAS-Mutant Tumors and BCR-ABL-Positive Leukemia

文献类型：期刊论文

作者Luo, Ziwei4,9; Lin, Chencen4,5; Yu, Chuwei6; Yuan, Changxian5; Wu, Wenyong6; Xu, Xiaowei7; Sun, Renhong8; Jia, Yan6; Wang, Yafang4; Shen, Jie10
刊名CANCER RESEARCH
出版日期2025-01-02
卷号85期号:1页码:101-117
ISSN号0008-5472
DOI10.1158/0008-5472.CAN-24-1093
通讯作者Jiang, Biao(jiangbiao@shanghaitech.edu.cn) ; Yang, Xiaobao(yang.xiaobao@gluetacs.com) ; Xie, Chengying(xiecy@lglab.ac.cn)
英文摘要Son of sevenless homolog 1 (SOS1) is an essential guanine nucleotide exchange factor for RAS that also plays a critical role in the activation of the small GTPase RAC mediated by BCR-ABL in leukemogenesis. Despite this, small-molecule inhibitors targeting SOS1 have shown limited efficacy in clinical trials for KRAS-mutant cancers, and their potential as a therapeutic approach for chronic myeloid leukemia (CML) remains largely unexplored. In this study, we developed a potent SOS1 proteolysis targeting chimera (PROTAC) SIAIS562055, which was designed by connecting a CRBN ligand to an analog of the SOS1 inhibitor BI-3406. SIAIS562055 exhibited sustained degradation of SOS1 and inhibition of downstream ERK pathways, resulting in superior antiproliferative activity compared with small-molecule inhibitors. SIAIS562055 also potentiated the activity of both KRAS inhibitors in KRAS-mutant cancers and ABL inhibitors in BCR-ABL-positive CML. In KRAS-mutant xenografts, SIAIS562055 displayed promising antitumor potency as a monotherapy and enhanced ERK inhibition and tumor regression when combined with KRAS inhibitors, overcoming acquired resistance. In CML cells, SIAIS562055 promoted the active uptake of BCR-ABL inhibitors by upregulating the carnitine/organic cation transporter SLC22A4. SIAIS562055 and BCR-ABL inhibitors synergistically enhanced inhibition of ABL phosphorylation and downstream signaling, demonstrating robust antitumor activities in both mouse xenografts and primary samples from patients with CML. In summary, this study suggests that PROTAC-mediated SOS1 degradation represents an effective therapeutic strategy for treating not only KRAS-mutant cancers but also BCR-ABL-harboring leukemia.Significance: The PROTAC SIAIS562055 sustainably degrades SOS1 and inhibits downstream ERK signaling, showing strong antiproliferative activity and synergistic effects with KRAS inhibitors in KRAS-mutant cancers and BCR-ABL inhibitors in chronic myeloid leukemia.
WOS关键词CHRONIC MYELOID-LEUKEMIA ; SELECTIVE INHIBITOR ; TYROSINE KINASE ; IMATINIB ; CANCER ; COMPLEX ; TRANSPORTERS ; MUTATION ; ELEMENTS ; AMN107
资助项目Lingang Laboratory[LG202101-01-06] ; National Key Research and Development Program of China[2022YFC3401500] ; Shanghai Municipal Government ; ShanghaiTech University ; Instrument Platform of Shanghai Institute for Advanced Immunochemical Studies at ShanghaiTech University, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai Jiao Tong University School of Medicine Affiliated Shanghai General Hospit
WOS研究方向Oncology
语种英语
WOS记录号WOS:001388150200002
出版者AMER ASSOC CANCER RESEARCH
源URL[http://119.78.100.183/handle/2S10ELR8/315273]  
专题中国科学院上海药物研究所
通讯作者Jiang, Biao; Yang, Xiaobao; Xie, Chengying
作者单位1.ShanghaiTech Univ, Sch Biomed Engn, Shanghai, Peoples R China
2.ShanghaiTech Univ, State Key Lab Adv Med Mat & Devices, Shanghai, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Dev Ctr, Shanghai, Peoples R China
4.ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, 93 Middle Huaxia Rd, Shanghai 201210, Peoples R China
5.ShanghaiTech Univ, Sch Phys Sci & Technol, Shanghai, Peoples R China
6.Lingang Lab, 319 Yueyang Rd, Shanghai 200031, Peoples R China
7.Shanghai Jiao Tong Univ, Affiliated Shanghai Gen Hosp, Dept Hematol, Sch Med, Shanghai, Peoples R China
8.Gluetacs Therapeut Shanghai Co Ltd, Bldg 20, Lane 218, Haiji Rd 6, Shanghai 201306, Peoples R China
9.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China
10.Shanghai Univ Tradit Chinese Med, Shuguang Hosp, SATCM Grade Lab Tradit Chinese Med Preparat 3, Dept Pharm, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Luo, Ziwei,Lin, Chencen,Yu, Chuwei,et al. Targeted Degradation of SOS1 Exhibits Potent Anticancer Activity and Overcomes Resistance in KRAS-Mutant Tumors and BCR-ABL-Positive Leukemia[J]. CANCER RESEARCH,2025,85(1):101-117.
APA Luo, Ziwei.,Lin, Chencen.,Yu, Chuwei.,Yuan, Changxian.,Wu, Wenyong.,...&Xie, Chengying.(2025).Targeted Degradation of SOS1 Exhibits Potent Anticancer Activity and Overcomes Resistance in KRAS-Mutant Tumors and BCR-ABL-Positive Leukemia.CANCER RESEARCH,85(1),101-117.
MLA Luo, Ziwei,et al."Targeted Degradation of SOS1 Exhibits Potent Anticancer Activity and Overcomes Resistance in KRAS-Mutant Tumors and BCR-ABL-Positive Leukemia".CANCER RESEARCH 85.1(2025):101-117.

入库方式： OAI收割

来源：上海药物研究所

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