Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, QC, H3T 1E2, Canada.
Division of Experimental Medicine, Department of Medicine, Faculty of Medicine, McGill University, Montreal, QC, H4A 3J1, Canada.
Nat Commun. 2019 May 13;10(1):2139. doi: 10.1038/s41467-019-10138-8.
Trastuzumab is integral to HER2+ cancer treatment, but its therapeutic index is narrowed by the development of resistance. Phosphorylation of the translation initiation factor eIF2α (eIF2α-P) is the nodal point of the integrated stress response, which promotes survival or death in a context-dependent manner. Here, we show an anti-tumor function of the protein kinase PKR and its substrate eIF2α in a mouse HER2+ breast cancer model. The anti-tumor function depends on the transcription factor ATF4, which upregulates the CDK inhibitor P21 and activates JNK1/2. The PKR/eIF2α-P arm is induced by Trastuzumab in sensitive but not resistant HER2+ breast tumors. Also, eIF2α-P stimulation by the phosphatase inhibitor SAL003 substantially increases Trastuzumab potency in resistant HER2+ breast and gastric tumors. Increased eIF2α-P prognosticates a better response of HER2+ metastatic breast cancer patients to Trastuzumab therapy. Hence, the PKR/eIF2α-P arm antagonizes HER2 tumorigenesis whereas its pharmacological stimulation improves the efficacy of Trastuzumab therapy.
曲妥珠单抗是治疗 HER2+癌症的重要药物，但由于其耐药性的发展，其治疗指数变窄。翻译起始因子 eIF2α 的磷酸化（eIF2α-P）是整合应激反应的节点，它以依赖于上下文的方式促进生存或死亡。在这里，我们在小鼠 HER2+乳腺癌模型中展示了蛋白激酶 PKR 及其底物 eIF2α 的抗肿瘤功能。这种抗肿瘤功能取决于转录因子 ATF4，它上调细胞周期蛋白依赖性激酶抑制剂 P21 并激活 JNK1/2。PKR/eIF2α-P 臂在敏感但不耐药的 HER2+乳腺癌肿瘤中被曲妥珠单抗诱导。此外，磷酸酶抑制剂 SAL003 对 eIF2α-P 的刺激大大增加了曲妥珠单抗在耐药 HER2+乳腺癌和胃癌肿瘤中的效力。增加的 eIF2α-P 预示着 HER2 转移性乳腺癌患者对曲妥珠单抗治疗的反应更好。因此，PKR/eIF2α-P 臂拮抗 HER2 肿瘤发生，而其药理学刺激可提高曲妥珠单抗治疗的疗效。
