Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
Molecular Pharmacology Program and Radiochemistry and Molecular Imaging Probes Core, Memorial Sloan Kettering Cancer Center, and Departments of Pharmacology and Radiology, Weill Cornell Medical College, New York, New York; and.
J Nucl Med. 2021 Mar;62(3):366-371. doi: 10.2967/jnumed.120.244897. Epub 2020 Jul 9.
Receptor tyrosine kinase (RTK) coexpression facilitates tumor resistance due to redundancies in the phosphatidylinositol-3'-kinase/protein kinase B and KRAS/extracellular-signal-regulated kinase signaling pathways, among others. Crosstalk between the oncogenic RTK hepatocyte growth factor receptor (MET), epidermal growth factor receptor (EGFR), and human epidermal growth factor receptor 2 (HER2) are involved in tumor resistance to RTK-targeted therapies. In a relevant renal cell carcinoma patient-derived xenograft model, we use the Zr-labeled anti-RTK antibodies (immuno-PET) onartuzumab, panitumumab, and trastuzumab to monitor MET, EGFR, and HER2 protein levels, respectively, during treatment with agents to which the model was resistant (cetuximab) or sensitive (INC280 and trametinib). Cetuximab treatment resulted in continued tumor growth, as well as an increase in all RTK protein levels at the tumor in vivo on immuno-PET and ex vivo at the cellular level. Conversely, after dual MET/mitogen-activated protein kinase inhibition, tumor growth was significantly blunted and corresponded to a decrease in RTK levels. These data show the utility of RTK-targeted immuno-PET to annotate RTK changes in protein expression and inform tumor response to targeted therapies.
受体酪氨酸激酶 (RTK) 共表达会导致肿瘤产生耐药性，这是由于磷脂酰肌醇-3'-激酶/蛋白激酶 B 和 KRAS/细胞外信号调节激酶等信号通路存在冗余。致癌 RTK 肝细胞生长因子受体 (MET)、表皮生长因子受体 (EGFR) 和人表皮生长因子受体 2 (HER2) 之间的串扰与 RTK 靶向治疗的肿瘤耐药性有关。在相关的肾细胞癌患者来源异种移植模型中，我们使用 Zr 标记的抗 RTK 抗体（免疫 PET）监测曲妥珠单抗、帕尼单抗和曲妥珠单抗分别针对 MET、EGFR 和 HER2 蛋白水平，在该模型耐药（西妥昔单抗）或敏感（INC280 和曲美替尼）的药物治疗期间。西妥昔单抗治疗导致肿瘤持续生长，并在体内免疫 PET 肿瘤和体外细胞水平上所有 RTK 蛋白水平增加。相反，在双重 MET/丝裂原活化蛋白激酶抑制后，肿瘤生长明显受到抑制，并且对应于 RTK 水平的降低。这些数据表明 RTK 靶向免疫 PET 可用于注释 RTK 蛋白表达的变化，并为肿瘤对靶向治疗的反应提供信息。
