Pool Martin, Terwisscha van Scheltinga Anton G T, Kol Arjan, Giesen Danique, de Vries Elisabeth G E, Lub-de Hooge Marjolijn N
Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands.
Eur J Nucl Med Mol Imaging. 2017 Aug;44(8):1328-1336. doi: 10.1007/s00259-017-3672-x. Epub 2017 Mar 19.
c-MET and its ligand hepatocyte growth factor are often dysregulated in human cancers. Dynamic changes in c-MET expression occur and might predict drug efficacy or emergence of resistance. Noninvasive visualization of c-MET dynamics could therefore potentially guide c-MET-directed therapies. We investigated the feasibility of Zr-labelled one-armed c-MET antibody onartuzumab PET for detecting relevant changes in c-MET levels induced by c-MET-mediated epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib resistance or heat shock protein-90 (HSP90) inhibitor NVP-AUY-922 treatment in human non-small-cell lung cancer (NSCLC) xenografts.
In vitro membrane c-MET levels were determined by flow cytometry. HCC827ErlRes, an erlotinib-resistant clone with c-MET upregulation, was generated from the exon-19 EGFR-mutant human NSCLC cell line HCC827. Mice bearing HCC827 and HCC827ErlRes tumours in opposite flanks underwent Zr-onartuzumab PET scans. The HCC827-xenografted mice underwent Zr-onartuzumab PET scans before treatment and while receiving biweekly intraperitoneal injections of 100 mg/kg NVP-AUY-922 or vehicle. Ex vivo, tumour c-MET immunohistochemistry was correlated with the imaging results.
In vitro, membrane c-MET was upregulated in HCC827ErlRes tumours by 213 ± 44% in relation to the level in HCC827 tumours, while c-MET was downregulated by 69 ± 9% in HCC827 tumours following treatment with NVP-AUY-922. In vivo, Zr-onartuzumab uptake was 26% higher (P < 0.05) in erlotinib-resistant HCC827ErlRes than in HCC827 xenografts, while HCC827 tumour uptake was 33% lower (P < 0.001) following NVP-AUY-922 treatment.
The results show that Zr-onartuzumab PET effectively discriminates relevant changes in c-MET levels and could potentially be used clinically to monitor c-MET status.
c-MET及其配体肝细胞生长因子在人类癌症中常发生失调。c-MET表达会出现动态变化，这可能预测药物疗效或耐药性的出现。因此，c-MET动态变化的无创可视化可能潜在地指导针对c-MET的治疗。我们研究了锆标记的单臂c-MET抗体奥那珠单抗PET检测在人非小细胞肺癌（NSCLC）异种移植模型中，由c-MET介导的表皮生长因子受体（EGFR）酪氨酸激酶抑制剂厄洛替尼耐药或热休克蛋白-90（HSP90）抑制剂NVP-AUY-922治疗所诱导的c-MET水平相关变化的可行性。
通过流式细胞术测定体外膜c-MET水平。从外显子19 EGFR突变的人NSCLC细胞系HCC827中产生了具有c-MET上调的厄洛替尼耐药克隆HCC827ErlRes。在双侧分别携带HCC827和HCC827ErlRes肿瘤的小鼠接受锆-奥那珠单抗PET扫描。接种HCC827的小鼠在治疗前以及接受每两周一次腹腔注射100 mg/kg NVP-AUY-922或赋形剂时接受锆-奥那珠单抗PET扫描。在体外，将肿瘤c-MET免疫组化与成像结果相关联。
在体外，HCC827ErlRes肿瘤中的膜c-MET相对于HCC827肿瘤中的水平上调了213±44%，而用NVP-AUY-922治疗后，HCC827肿瘤中的c-MET下调了69±9%。在体内，厄洛替尼耐药的HCC827ErlRes中锆-奥那珠单抗摄取比HCC827异种移植瘤高26%（P<0.05），而在接受NVP-AUY-922治疗后，HCC827肿瘤摄取降低了33%（P<0.001）。
结果表明，锆-奥那珠单抗PET能有效区分c-MET水平的相关变化，可能在临床上用于监测c-MET状态。
