University of Chicago, USA.
Cancer Biol Ther. 2011 Jul 1;12(1):9-46. doi: 10.4161/cbt.12.1.15747.
RON (MST1R) is one of two members of the MET receptor tyrosine kinase family, along with parent receptor MET. RON has a putative role in several cancers, but its expression and function is poorly characterized in gastroesophageal adenocarcinoma. A recognized functional role of MET tyrosine kinase in gastroesophageal cancer has led to early phase clinical trials using MET inhibitors, with unimpressive results. Therefore, the role of RON in gastroesophageal cancer, as well as its role in cooperative signaling with MET and as a mechanism of resistance to MET inhibition, was studied in gastroesophageal tissues and cell lines. By IHC, RON was highly over-expressed in 74% of gastroesophageal samples (n=94), and over-expression was prognostic of poor survival (p=0.008); RON and MET co-expression occurred in 43% of samples and was prognostic of worst survival (p=0.03). High MST1R gene copy number by quantitative polymerase chain reaction, and confirmed by fluorescence in situ hybridization and/or array comparative genomic hybridization, was seen in 35.5% (16/45) of cases. High MST1R gene copy number correlated with poor survival (p=0.01), and was associated with high MET and ERBB2 gene copy number. A novel somatic MST1R juxtamembrane mutation R1018G was found in 11% of samples. RON signaling was functional in cell lines, activating downstream effector STAT3, and resulted in increased viability over controls. RON and MET co-stimulation assays led to enhanced malignant phenotypes over stimulation of either receptor alone. Growth inhibition as evidenced by viability and apoptosis assays was optimal using novel blocking monoclonal antibodies to both RON and MET, versus either alone. SU11274, a classic MET small molecule tyrosine kinase inhibitor, blocked signaling of both receptors, and proved synergistic when combined with STAT3 inhibition (combination index < 1). These preclinical studies define RON as an important novel prognostic marker and therapeutic target for gastroesophageal cancer warranting further investigation.
RON（MST1R）是 MET 受体酪氨酸激酶家族的两个成员之一，另一个是亲本受体 MET。RON 在几种癌症中具有潜在作用，但在胃食管腺癌中的表达和功能特征描述不足。MET 酪氨酸激酶在胃食管癌症中的公认功能作用导致了使用 MET 抑制剂的早期临床试验，但结果并不理想。因此，RON 在胃食管癌症中的作用，以及其与 MET 的合作信号传导作用以及作为对 MET 抑制的耐药机制的作用，在胃食管组织和细胞系中进行了研究。通过免疫组化，RON 在 74%的胃食管样本（n=94）中高度过表达，过表达与生存不良相关（p=0.008）；RON 和 MET 的共表达发生在 43%的样本中，与最差的生存相关（p=0.03）。通过定量聚合酶链反应检测到 MST1R 基因拷贝数高，通过荧光原位杂交和/或阵列比较基因组杂交证实，在 35.5%（16/45）的病例中可见。高 MST1R 基因拷贝数与生存不良相关（p=0.01），并且与高 MET 和 ERBB2 基因拷贝数相关。在 11%的样本中发现了一种新的体细胞 MST1R 跨膜突变 R1018G。RON 信号在细胞系中是功能性的，激活下游效应因子 STAT3，导致细胞活力比对照增加。RON 和 MET 共刺激试验导致刺激两个受体的恶性表型增强，而单独刺激任何一个受体都没有。通过活力和凋亡测定证明，使用针对 RON 和 MET 的新型阻断单克隆抗体的生长抑制作用优于单独使用任何一种抗体。SU11274 是一种经典的 MET 小分子酪氨酸激酶抑制剂，阻断了两个受体的信号传导，并且当与 STAT3 抑制联合使用时证明具有协同作用（组合指数 <1）。这些临床前研究将 RON 定义为胃食管癌症的一个重要的新的预后标志物和治疗靶点，值得进一步研究。
