Increased mTOR activity and RICTOR copy number in small cell lung carcinoma progression

Abstract

Small cell lung carcinoma (SCLC) is a highly malignant cancer with early metastatic dissemination and poor clinical outcomes. Mutations in the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway, including the frequently occurring rapamycin-insensitive protein (RICTOR) amplification, have been described in these tumours. Moreover, the associated mTOR hyperactivity could be exploited for personalised treatment. Our aim was to study mTOR activity, RICTOR amplification, and their role during SCLC progression. In situ mTOR activity and Rictor expression were characterised by immunohistochemistry in 50 primary and 50 brain metastatic tumours, and 14 paired SCLC patient samples. RICTOR copy number changes were analysed by fluorescence in situ hybridisation of the paired SCLC patient samples and in vivo experiments. Additionally, in vitro sensitivity to cisplatin and mTOR inhibitors was evaluated in SCLC cell lines harbouring RICTOR amplification and other mTOR pathway mutations. High Rictor expression and mTOR complex 2 (mTORC2) hyperactivity were significantly associated with brain metastases and worse overall survival. An increase in RICTOR copy number was observed in paired samples during progression. The importance of these alterations was confirmed both by the sensitising effect of vistusertib in vitro and the RICTOR copy number/expression changes in xenografts. Our study highlights the role of mTORC2 in SCLC progression. Early detection of RICTOR amplification in primary tumours and targeting mTORC2 in these cases may represent a promising novel strategy to develop personalised therapy for metastasis prevention.