Background: Despite treatment advances, most lung cancer patient will still receive platinum-based chemotherapy and platinum resistance remains a serious clinical problem. RICTOR is a key component of the mTOR complex 2. Activation of RICTOR signaling has been suggested to play critical roles in regulating cancer cell migration, invasion and metastasis. A recent study indicates that RICTOR contributes to cisplatin resistance in human ovarian cancer cells. We hypothesize that activation of RICTOR signaling is associated with platinum resistance in lung cancer. Thus, we tested platinum sensitivities in lung cancer cells and xenograft mouse models with different RICTOR levels. Results: RICTOR expression was found in 79% (99/125) of primary lung tumors and 67% (24/36) lung cancer cells by immunohistochemistry. The expression of RICTOR was significantly higher in squamous cell lung cancer in comparison to lung adenocarcinoma (P<0.05). Overexpression of RICTOR in the Ba/F3 cells resulted in significant cisplatin resistance, whereas down-regulation of RICTOR in H23, HCC827 and H1703 lung cancer cells led to significantly improved cisplatin sensitivity. In addition, the combination of cisplatin and RICTOR knockdown significantly promoted more apoptosis than single treatment. To test the in vivo effects of RICTOR on platinum sensitivity, we performed HCC827 xenograft mouse experiments. Cisplatin alone and RICTOR knockdown alone significantly inhibited tumor growth. Moreover, RICTOR knockdown significantly increased the sensitivities to cisplatin in the xenografts and the combination led to more pronounced tumor reduction than either alone (P<0.05). Conclusion: Our study provides a novel resistance mechanism to platinum treatment in lung cancer and may serve as basis to target RICTOR to overcome platinum resistance.

Citation Format: Haiying Cheng, Ni Fan, Alain Borczu, Huijie Liu, Aditi Singh, Feng Wang, Balazs Halmos, Roman Perez-Soler. RICTOR modulation regulates cisplatin sensitivity in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 905.