Fan Hao, Hu Xuefei, Cao Fuao, Zhou Leqi, Wen Rongbo, Shen Hao, Fu Yating, Zhu Xiaoming, Jia Hang, Liu Zixuan, Wang Guimin, Yu Guanyu, Chang Wenjun, Zhang Wei
Department of Colorectal Surgery, Changhai Hospital, Naval Medical University, Shanghai, China.
Department of Navy Environmental and Occupational Health, Faculty of Naval Medicine, Naval Medical University, Shanghai, China.
NPJ Precis Oncol. 2024 Jul 16;8(1):144. doi: 10.1038/s41698-024-00650-6.
Protein tyrosine phosphatase SHP2 activates RAS signaling, which is a novel target for colorectal cancer (CRC) therapy. However, SHP2 inhibitor monotherapy is ineffective for metastatic CRC and a combination therapy is required. In this study, we aimed to improve the antitumor efficacy of SHP2 inhibition and try to explore the resistance mechanism of SHP2 inhibitor. Results showed that WWP1 promoted the proliferation of CRC cells. Genetic or pharmacological inhibition of WWP1 enhanced the effect of SHP2 inhibitor in suppressing tumor growth in vitro and in vivo. WWP1 may mediate feedback reactivation of AKT signaling following SHP2 inhibition. Furthermore, nomogram models constructed with IHC expression of WWP1 and SHP2 greatly improved the accuracy of prognosis prediction for patients with CRC. Our findings indicate that WWP1 inhibitor I3C can synergize with SHP2 inhibitor and is expected to be a new strategy for clinical trials in treating advanced CRC patients.
蛋白酪氨酸磷酸酶SHP2激活RAS信号通路，这是结直肠癌（CRC）治疗的一个新靶点。然而，SHP2抑制剂单药治疗对转移性CRC无效，需要联合治疗。在本研究中，我们旨在提高SHP2抑制的抗肿瘤疗效，并探索SHP2抑制剂的耐药机制。结果表明，WWP1促进CRC细胞的增殖。对WWP1进行基因或药物抑制可增强SHP2抑制剂在体外和体内抑制肿瘤生长的效果。WWP1可能介导SHP2抑制后AKT信号通路的反馈性重新激活。此外，用WWP1和SHP2的免疫组化表达构建的列线图模型大大提高了CRC患者预后预测的准确性。我们的研究结果表明，WWP1抑制剂I3C可与SHP2抑制剂协同作用，有望成为治疗晚期CRC患者临床试验的新策略。
