Abstract A283: PI3K/Akt/mTOR dual inhibitors have an advantage over single inhibitors in overcoming prostate cancer radioresistance.

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Abstract Purpose: Radioresistance is a major problem in prostate cancer (CaP) radiotherapy (RT). The phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR signaling pathway plays a central role in cancer metastasis and radioresistance. This study aimed to evaluate the effects of combination of dual or single inhibitors targeting PI3K/Akt/mTOR pathway proteins with RT in CaP radioresistant (RR) cells in vitro. Experimental Design: Three CaP-RR cell lines (PC-3RR, DU145RR, and LNCaPRR) were established in our laboratory by radiation treatment and their radioresistance was confirmed by colony assay. The half maximal inhibitory concentration (IC50) values of four inhibitors including two dual inhibitors (BEZ235 and PI103) and two single inhibitors (BKM120 and Rapamycin) were tested by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in CaP RR cells. Combination of 1/2 IC50 doses of each inhibitor with RT was examined to decide which inhibitor has a better capability to improve radiosensitivity of CaP-RR cells by cologenic assay and apoptosis assays. Results: We found that CaP-RR cells are associated with epithelial-mesenchymal transition (EMT) and enhanced cancer stem cell phenotypes, and the activation of PI3K/Akt/mTOR signaling pathway. We also found that the combination of single inhibitor either BKM120 (targeting PI3k) or rapamycin (Targeting mTOR) with RT had limited capability to improve radiosensitivity, including less regression of colony formation and inducing less apoptosis in CaP RR cells, whereas dual inhibitor BEZ235 or PI103 combined with RT could effectively improve radiosensitivity, obviously inhibit CaP RR cells in colony ability (P<0.05), and induce more apoptosis (P<0.05). Conclusions: Our findings suggest that PI3K/Akt/mTOR pathway is actively involved in CaP radioresistance and the dual PI3K/Akt/mTOR inhibitors (BEZ235 and PI103) have obvious advantages over single inhibitors in sensitizing radiation therapy and overcome CaP radioresistance. Using a PI3K/mTOR dual inhibitor with RT is a promising modality for the treatment of CaP to overcome radioresistance and this combination approach is worthwhile for future animal study and clinical trials. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A283. Citation Format: Lei Chang, Peter Graham, Jingli Hao, Jie Ni, Joseph Bucci, Paul Cozzi, John Kearseley, Yong Li. PI3K/Akt/mTOR dual inhibitors have an advantage over single inhibitors in overcoming prostate cancer radioresistance. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A283.