Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, 149, 13th Street, Charlestown, MA, 02129, USA.
Institute for Innovation in Imaging, Massachusetts General Hospital, Boston, MA, USA.
Mol Imaging Biol. 2023 Apr;25(2):353-362. doi: 10.1007/s11307-022-01763-9. Epub 2022 Aug 12.
New generation of receptor tyrosine kinase inhibitors (RTKIs) have shown to improve survival in many solid tumors. However, an imaging biomarker is needed for patient selection and prediction of treatment response. This study evaluates the use of quantitative changes of HER3 on Ga-NOTA-HER3P1 PET/MRI for prediction of early response to pan-RTKIs in gastric cancer (GCa).
GCa cell lines were evaluated for expression of RTKs, and downstream signaling pathways (AKT and MAPK). Cell viability was assessed following 24-72 h of treatment with 0.01-1 µmol/L of afatinib, a pan-RTKI. HER3-expressing afatinib-sensitive (NCI-N87) and resistant cells (SNU16) were selected for evaluation of changes in RTKs expression and downstream pathways, with 24-72 h of 0.1 µmol/L afatinib treatment. Ga-NOTA-HER3P1 PET/MRI was performed in subcutaneous NCI-N87 and SNU16 xenografts (nu:nu, n = 12/group) at baseline and 4 days after afatinib treatment (10 mg/kg, PO, daily). Temporal changes in PET measures were correlated to HER3 expression in tumors, tumor growth rate, and treatment response.
With afatinib therapy, NCI-N87 cells showed increased total HER3 expression, and reduction of other RTKs and downstream nodes within 72 h, while SNU16 cells showed no significant change in total HER3 and downstream nodes. Ga-HER3P1 PET/MRI showed increased uptake in NCI-N87 and no significant change in SNU16 tumors (day 4 vs. baseline SUV: 3.8 ± 0.7 vs. 1.6 ± 0.6, p < 0.05 in NCI-N87, and 1.5 ± 0.7 vs. 1.7 ± 0.7, p > 0.05 in SNU16). These findings were in concordance with HER3 expression in histopathological analyses and tumor growth over 3 weeks of treatment (mean tumor volume in treated vs. control: 11 ± 17 mm vs. 293 ± 79 mm, p < 0.001 in NCI-N87, and 238 ± 91 mm vs. 282 ± 35 mm, p > 0.05 in SNU16).
Quantitative changes in HER3 PET could be used to predict response to pan-RTKI within few days after initiation of treatment and can help with personalizing GCa management.
新一代受体酪氨酸激酶抑制剂（RTKIs）已被证明可改善许多实体瘤的生存率。然而，需要一种成像生物标志物来选择患者并预测治疗反应。本研究评估了定量变化在 Ga-NOTA-HER3P1 PET/MRI 上 HER3 用于预测胃癌（GCa）中 pan-RTKIs 的早期反应。
评估了 GCa 细胞系中 RTKs 及其下游信号通路（AKT 和 MAPK）的表达。用 0.01-1µmol/L 的 afatinib（一种 pan-RTKI）处理 24-72 小时后，评估细胞活力。选择表达 HER3 的 afatinib 敏感（NCI-N87）和耐药细胞（SNU16），并在 0.1µmol/L afatinib 处理 24-72 小时后评估 RTKs 表达和下游通路的变化。在皮下 NCI-N87 和 SNU16 异种移植瘤（nu：nu，n=12/组）中进行 Ga-NOTA-HER3P1 PET/MRI 检查，分别在基线和 afatinib 治疗后 4 天（10mg/kg，PO，每日）。PET 测量的时间变化与肿瘤中 HER3 表达、肿瘤生长速度和治疗反应相关。
在 afatinib 治疗下，NCI-N87 细胞在 72 小时内显示出总 HER3 表达增加，其他 RTKs 和下游节点减少，而 SNU16 细胞的总 HER3 和下游节点没有明显变化。Ga-HER3P1 PET/MRI 显示 NCI-N87 肿瘤摄取增加，而 SNU16 肿瘤无明显变化（第 4 天与基线 SUV：3.8±0.7 与 1.6±0.6，p<0.05；1.5±0.7 与 1.7±0.7，p>0.05）。这些发现与组织病理学分析和治疗 3 周内的肿瘤生长情况一致（治疗组与对照组的平均肿瘤体积：11±17mm 与 293±79mm，p<0.001；238±91mm 与 282±35mm，p>0.05）。
HER3 PET 的定量变化可用于预测 pan-RTKI 治疗后几天内的反应，并有助于个体化 GCa 管理。
