Kang Di, Wang Yanping, Lin Yiwei, Ma Wen Wee, Morgensztern Daniel, Leventakos Konstantinos, Bi Chao, Ding Yuli, Xiong Jing, Yan Man, Sun Xin, Wang Peng, Ma Cunbo, Wang Yinxiang
Department of Pharmacology, Jacobio Pharmaceuticals Co., Ltd., Beijing, China.
Department of Translational Medicine, Jacobio (US) Pharmaceuticals, Inc., Burlington, Massachusetts.
Clin Cancer Res. 2025 Jul 15;31(14):3019-3032. doi: 10.1158/1078-0432.CCR-24-3691.
Recent advances have seen the development of targeted therapeutics against the receptor tyrosine kinase (RTK)/RAS/MAPK pathway, which, when aberrantly activated, drives the malignant transformation of many cancer indications. However, the efficacy of inhibitors targeting single molecules is dampened by pathway feedback activation and acquired drug resistance. We seek to evaluate the application of JAB-3312 (sitneprotafib), a potent inhibitor of SHP2, in RTK/RAS/MAPK pathway-targeted combination therapies. Furthermore, SHP2 plays a vital role in PD-1-mediated immunosuppression. The rational combination of JAB-3312 with PD-1 blocking therapies is also explored.
Biochemical and cellular assays were applied to evaluate the potency of JAB-3312 in SHP2 inhibition. Tumor cell lines and cell line- and patient-derived xenografts were used to test different combinations of JAB-3312 with KRASG12C, MEK, EGFR, and PD-1 inhibitors.
JAB-3312 produced potent in vitro inhibition of SHP2 activity and downstream ERK phosphorylation, with IC50 values of 1.44 nmol/L and 0.68 to 4.84 nmol/L, respectively. When used in combination, JAB-3312 significantly increased the antitumor activity of the KRASG12C inhibitor glecirasib in naïve and resistant models. The combination of JAB-3312 with MEK inhibitors significantly delayed RTK signaling reactivation and enhanced tumor growth inhibition in KRAS-mutated cancer models. The JAB-3312-osimertinib combination exhibited great efficacy in osimertinib-resistant non-small cell lung cancer models. Additionally, JAB-3312 enhanced the efficacy of PD-1 blockade therapies by promoting an antitumor microenvironment. Representative cases of patients who responded to the combination therapies from two ongoing clinical trials (NCT05288205 and NCT04720976) were reported.
JAB-3312 in combination with RTK/RAS/MAPK or PD-1 blockade therapies is a promising strategy that warrants further clinical investigation.
近年来，针对受体酪氨酸激酶（RTK）/RAS/MAPK通路的靶向治疗药物取得了进展，该通路异常激活时会驱动多种癌症指征的恶性转化。然而，靶向单一分子的抑制剂的疗效会因通路反馈激活和获得性耐药而受到影响。我们旨在评估SHP2强效抑制剂JAB-3312（sitneprotafib）在RTK/RAS/MAPK通路靶向联合治疗中的应用。此外，SHP2在PD-1介导的免疫抑制中起着至关重要的作用。还探讨了JAB-3312与PD-1阻断疗法的合理联合应用。
应用生化和细胞试验评估JAB-3312抑制SHP2的效力。使用肿瘤细胞系以及细胞系和患者来源的异种移植模型来测试JAB-3312与KRASG12C、MEK、EGFR和PD-1抑制剂的不同联合应用。
JAB-3312在体外对SHP2活性和下游ERK磷酸化产生强效抑制作用，IC50值分别为1.44 nmol/L和0.68至4.84 nmol/L。联合使用时，JAB-3312在未治疗和耐药模型中显著增强了KRASG12C抑制剂glecirasib的抗肿瘤活性。在KRAS突变的癌症模型中，JAB-3312与MEK抑制剂联合使用可显著延迟RTK信号重新激活并增强肿瘤生长抑制作用。JAB-3312与奥希替尼联合应用在奥希替尼耐药的非小细胞肺癌模型中显示出强大的疗效。此外，JAB-3312通过促进抗肿瘤微环境增强了PD-1阻断疗法的疗效。报告了两项正在进行的临床试验（NCT05288205和NCT04720976）中对联合治疗有反应的患者的代表性病例。
JAB-3312与RTK/RAS/MAPK或PD-1阻断疗法联合应用是一种有前景的策略，值得进一步开展临床研究。
