Luo Ziwei, Lin Chencen, Yu Chuwei, Yuan Changxian, Wu Wenyong, Xu Xiaowei, Sun Renhong, Jia Yan, Wang Yafang, Shen Jie, Wang Dingyan, Wang Sinan, Jiang Hualiang, Jiang Biao, Yang Xiaobao, Xie Chengying
School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, China.
Cancer Res. 2025 Jan 2;85(1):101-117. doi: 10.1158/0008-5472.CAN-24-1093.
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.
七号染色体失活同源物1（SOS1）的儿子是RAS的一种必需鸟嘌呤核苷酸交换因子，在白血病发生过程中由BCR-ABL介导的小GTP酶RAC激活中也起着关键作用。尽管如此，针对SOS1的小分子抑制剂在KRAS突变癌症的临床试验中显示出有限的疗效，其作为慢性髓性白血病（CML）治疗方法的潜力在很大程度上仍未得到探索。在本研究中，我们开发了一种有效的SOS1蛋白酶靶向嵌合体（PROTAC）SIAIS562055，它是通过将CRBN配体与SOS1抑制剂BI-3406的类似物连接而设计的。SIAIS562055表现出SOS1的持续降解和下游ERK途径的抑制，与小分子抑制剂相比，具有更强的抗增殖活性。SIAIS562055还增强了KRAS突变癌症中KRAS抑制剂和BCR-ABL阳性CML中ABL抑制剂的活性。在KRAS突变异种移植模型中，SIAIS562055作为单一疗法显示出有前景的抗肿瘤效力，并且与KRAS抑制剂联合使用时增强了ERK抑制和肿瘤消退，克服了获得性耐药。在CML细胞中，SIAIS562055通过上调肉碱/有机阳离子转运体SLC22A4促进BCR-ABL抑制剂的主动摄取。SIAIS562055和BCR-ABL抑制剂协同增强对ABL磷酸化和下游信号传导的抑制，在小鼠异种移植模型和CML患者的原代样本中均显示出强大的抗肿瘤活性。总之，本研究表明PROTAC介导的SOS1降解不仅是治疗KRAS突变癌症的有效治疗策略，也是治疗携带BCR-ABL的白血病的有效策略。意义：PROTAC SIAIS562055可持续降解SOS1并抑制下游ERK信号传导，在KRAS突变癌症中显示出强大的抗增殖活性以及与KRAS抑制剂的协同作用，在慢性髓性白血病中与BCR-ABL抑制剂也有协同作用。
