Despite recent advances, clinically-relevant oncogenic drivers have not been identified in about half of lung adenocarcinormas. Here, we report rictor (rapamycin-insensitive companion of mTOR) amplification as a novel genetic abnormality in a young patient with non-small cell lung cancer. This male patient was a never smoker and was diagnosed with lung adenocarcinorma at the age of 18. He initially presented with refractory cough and persistent left lung lesions. Pathology was consistent with lung adenocarcinorma, poorly differentiated. Extensive molecular testing was negative for common genetic alterations in K-RAS, EGFR, ALK, HER2, RET, AKT, PIK3CA, BRAF and ROS1. His tumor was subsequently subjected to next generation DNA sequencing (FoundationOne, Foundation Medicine, Cambridge, MA) targeting a cohort of more than 180 cancer-related genes. This analysis identified rictor amplification of at least 6 copies as the sole DNA abnormality. Immunohistochemistry further documented rictor overexpression in the patient's lung tumor. The neoplastic lung tissue exhibited diffuse and strong cytoplasmic staining for rictor, compared to surrounding non-neoplastic tissues. Furthermore, the tumor tissue showed diffuse overexpression of phospho-S473 Akt, an essential downstream target of rictor.

Rictor is a key component of mTORC2 complex, where it modifies actin cytoskeleton organization, cell proliferation and survival. Activation of rictor signaling has been suggested to play critical roles in regulating cancer cell migration, invasion and metastasis in breast, ovarian, and colorectal cancers and gliomas. To our knowledge, this is the first report of rictor amplification in lung cancer. Moreover, we found that blockade of the rictor-mTORC2 pathway by siRNA-mediated rictor knockdown or with pharmacological inhibitors led to decreased phosphorylation of S473-AKT and growth inhibition in lung cancer cell lines. Thus, rictor amplification may represent a potential novel target in lung cancer. We will perform further studies to determine whether rictor amplification is a unique molecular subtype of lung cancer. Further, we hope to identify which targeted drugs are active against tumors with rictor amplification and overexpression.

Citation Format: Haiying Cheng, Bilal Piperdi, Edward L. Schwartz, Changcheng Zhu, Zhenfeng Zhang, Balazs Halmos, Vincent Miller, Roman Perez-Soler. Identification of a novel genetic abnormality, the amplification of rictor (rapamycin-insensitive companion of mTOR), in a patient with non-small cell lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2033. doi:10.1158/1538-7445.AM2013-2033