RICTOR (Rapamycin-insensitive companion of mTOR protein) is a key component of mTORC2 (the mammalian target of rapamycin complex 2). One of the most-recognized targets for RICTOR-mTORC2 is AKT (Ser473). RICTOR also carries functions independent of mTORC2. RICTOR signaling has been suggested to play key roles in regulating cancer cell migration, invasion and metastasis in breast, ovarian, colorectal cancers and gliomas. The potential roles of RICTOR in lung cancer remain to be elucidated. We first examined the expression profile of RICTOR in primary lung tumor specimens and in lung cancer cell lines by immunohistochemistry. Among 125 FFPE patients' specimen, ninety nine were stained positive for RICTOR (intensity 1+ to 3+). More interestingly, the RICTOR IHC expression is stronger in squamous cell lung cancer in comparison to adenocarcinoma. Furthermore, twenty four out of 36 lung cancer cell lines showed positive RICTOR IHC staining. Thus, RICTOR is expressed in most lung tumors. To investigate the role of RICTOR in lung cancer cell growth, we found that RICTOR knockdown by siRNA reduced colony formation in A549, HCC827 and Calu3 cells, regardless of KRAS or EGFR mutational status (A549 is KRAS mutated whereas HCC827 is EGFR mutated). Western blot confirmed RICTOR knockdown and also decreased level of its downstream pAKT S473. We further blocked RICTOR signaling by utilizing inducible shRNAs of RICTOR. Similar inhibition of lung cancer cell growth was observed. Moreover, to test the in vivo role of RICTOR, we preformed xenograft mouse experiments. When RICTOR was inducibly knockdown by the presence of doxycycline, the growth of A549 lung tumor xenografts was markedly reduced by 60% (P<0.05). Taken together, our study provides the rational basis for a potential RICTOR-targeted therapy in lung cancer.
Citation Format: Haiying Cheng, Yiyu Zou, Alain Borczuk, Wanglong Qiu, Bilal Piperdi, Mimi Kim, Balazs Halmos, Roman Perez-Soler. The mTORC2 component RICTOR plays a key role in lung cancer cell growth. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3526. doi:10.1158/1538-7445.AM2014-3526