BACKGROUND: Inhibitors of the mammalian target of rapamycin (mTOR) are emerging as promising therapies for metastatic renal cell carcinoma (RCC). Because rational treatment strategies require understanding the activation status of the underlying signaling pathway being targeted at the desired stage of disease, the authors examined the activation status of different components of the mTOR pathway in RCC metastases and matched primary tumors. METHODS: The authors immunostained metastatic RCC samples from 132 patients and a subset of 25 matched primary RCCs with antibodies against phosphatidylinositol 3'-kinase, PTEN, phospho-Akt, phospho-mTOR, and p70S6. PTEN genomic status was assessed by fluorescent in situ hybridization. Marker expression was correlated to clinicopathologic variables and to survival. RESULTS: The mTOR pathway showed widespread activation in RCC metastases of various sites with strong correlation between different components of this signaling cascade (P<.0001), but without significant PTEN genomic deletion. Only cytoplasmic phospho-mTOR showed independent prognostic significance (P = .029) and fidelity between primary RCCs and their matched metastases (P = .004). CONCLUSIONS: Activation of various components of the mTOR signaling pathway in metastatic RCC lesions across various tumor histologies, nuclear grades, and metastatic sites suggests the potential for vertical blockade of multiple steps of this pathway. Patient selection may be improved by mTOR immunostaining of primary RCC.
BACKGROUND: Inhibitors of the mammalian target of rapamycin (mTOR) are emerging as promising therapies for metastatic renal cell carcinoma (RCC). Because rational treatment strategies require understanding the activation status of the underlying signaling pathway being targeted at the desired stage of disease, the authors examined the activation status of different components of the mTOR pathway in RCC metastases and matched primary tumors. METHODS: The authors immunostained metastatic RCC samples from 132 patients and a subset of 25 matched primary RCCs with antibodies against phosphatidylinositol 3'-kinase, PTEN, phospho-Akt, phospho-mTOR, and p70S6. PTEN genomic status was assessed by fluorescent in situ hybridization. Marker expression was correlated to clinicopathologic variables and to survival. RESULTS: The mTOR pathway showed widespread activation in RCC metastases of various sites with strong correlation between different components of this signaling cascade (P<.0001), but without significant PTEN genomic deletion. Only cytoplasmic phospho-mTOR showed independent prognostic significance (P = .029) and fidelity between primary RCCs and their matched metastases (P = .004). CONCLUSIONS: Activation of various components of the mTOR signaling pathway in metastatic RCC lesions across various tumor histologies, nuclear grades, and metastatic sites suggests the potential for vertical blockade of multiple steps of this pathway. Patient selection may be improved by mTOR immunostaining of primary RCC.
Authors: Jianing Xu; Can G Pham; Steven K Albanese; Yiyu Dong; Toshinao Oyama; Chung-Han Lee; Vanessa Rodrik-Outmezguine; Zhan Yao; Song Han; David Chen; Daniel L Parton; John D Chodera; Neal Rosen; Emily H Cheng; James J Hsieh Journal: J Clin Invest Date: 2016-08-02 Impact factor: 14.808
Authors: Christopher E Barbieri; Arul M Chinnaiyan; Seth P Lerner; Charles Swanton; Mark A Rubin Journal: Eur Urol Date: 2016-08-25 Impact factor: 20.096
Authors: Zhi Rong Qian; Monica Ter-Minassian; Jennifer A Chan; Yu Imamura; Susanne M Hooshmand; Aya Kuchiba; Teppei Morikawa; Lauren K Brais; Anastassia Daskalova; Rachel Heafield; Xihong Lin; David C Christiani; Charles S Fuchs; Shuji Ogino; Matthew H Kulke Journal: J Clin Oncol Date: 2013-08-26 Impact factor: 44.544
Authors: Brian Shuch; Christopher J Ricketts; Cathy D Vocke; Takefumi Komiya; Lindsay A Middelton; Eric C Kauffman; Maria J Merino; Adam R Metwalli; Phillip Dennis; W Marston Linehan Journal: J Urol Date: 2013-06-11 Impact factor: 7.450