1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary H-1085.
Division of Hematology and Medical Oncology, Mayo Clinic, Jacksonville, FL 32224.
Hum Pathol. 2019 Nov;93:74-80. doi: 10.1016/j.humpath.2019.08.018. Epub 2019 Aug 24.
Small cell lung carcinoma (SCLC) accounts for approximately 15% of all lung cancers and remains a challenging disease, with no significant improvement in the field of targeted therapies. The RICTOR gene (rapamycin-insensitive companion of mTOR [mammalian target of rapamycin]), which encodes a key structural (scaffold) protein of mTOR complex 2), has recently been identified as one of the most frequently amplified genes and a potential therapeutic target in SCLC. The aim of this study was to compare immunohistochemical (IHC) expression of Rictor and phospho-Akt (a downstream target of mTOR complex 2) with RICTOR amplification as detected by fluorescence in situ hybridization (FISH) in SCLC. RICTOR FISH and Rictor and phospho-Akt IHC staining were performed on 100 formalin-fixed, paraffin-embedded SCLC samples. RICTOR amplification was detected in 15 samples (15%). IHC positivity for Rictor and phospho-Akt was observed in 37 (37%) and 42 (42%) samples, respectively. Considering FISH as the diagnostic standard, the sensitivity and specificity of Rictor IHC were 93% and 73%, whereas the sensitivity and specificity of phospho-Akt IHC were 80% and 65%, respectively. Rictor expression was higher in distant metastases than in primary tumor samples and lymph node metastases. There was no association between RICTOR amplification and clinical outcome. However, high expression of either Rictor or phospho-Akt was associated with significantly decreased overall survival. In conclusion, IHC expression of Rictor correlates highly with RICTOR amplification. Therefore, Rictor IHC can be used as a cost-effective method to select patients for RICTOR FISH and, potentially, for mTORC1/2 inhibitor therapy.
小细胞肺癌（SCLC）约占所有肺癌的 15%，仍然是一种具有挑战性的疾病，在靶向治疗领域没有显著的改善。RICTOR 基因（雷帕霉素不敏感的 mTOR[哺乳动物雷帕霉素靶蛋白]伴侣），编码 mTOR 复合物 2 的关键结构（支架）蛋白之一，最近被确定为 SCLC 中最常扩增的基因之一和潜在的治疗靶点。本研究旨在比较免疫组织化学（IHC）表达的 Rictor 和磷酸化 Akt（mTOR 复合物 2 的下游靶点）与荧光原位杂交（FISH）检测的 SCLC 中的 RICTOR 扩增。对 100 例福尔马林固定、石蜡包埋的 SCLC 样本进行了 RICTOR FISH 和 Rictor 和磷酸化 Akt IHC 染色。在 15 个样本（15%）中检测到 RICTOR 扩增。分别有 37（37%）和 42（42%）个样本的 Rictor 和磷酸化 Akt IHC 呈阳性。考虑到 FISH 作为诊断标准，Rictor IHC 的敏感性和特异性分别为 93%和 73%，而磷酸化 Akt IHC 的敏感性和特异性分别为 80%和 65%。Rictor 的表达在远处转移中高于原发性肿瘤样本和淋巴结转移。RICTOR 扩增与临床结局之间没有关联。然而，Rictor 或磷酸化 Akt 的高表达与总生存时间明显缩短相关。总之，Rictor 的 IHC 表达与 RICTOR 扩增高度相关。因此，Rictor IHC 可作为一种经济有效的方法，用于选择 RICTOR FISH 的患者，并且可能用于 mTORC1/2 抑制剂治疗。
