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Abstract B02: Combined inhibition of mTOR and Src family kinases enhances treatment effects in prostate cancer cells

Hyperactivated Akt/mTOR pathway and Src family kinases (SFKs) pathway commonly occur in prostate cancer that is highly associated with disease progression and poor prognosis. Therefore, small-molecule inhibitors targeting these pathways have been studied extensively for the treatment of advanced prostate cancer. Nevertheless, clinical observation suggests that individual treatment with either inhibitor only yields limited antitumor effects in patients. One possible interpretation is that these signaling pathways are redundant, such that blocking one pathway is not sufficient to yield considerable efficacies. In this regard, we combined mTOR inhibitor rapamycin and Src inhibitor dasatinib to detect functional behaviors in prostate cancer cells. Cell proliferation was detected by MTT, and clonogenic survival was tested by colony formation assay. Cell migration was assessed by “wound-healing” scratch assay. Protein expression was detected by Western blot analysis. We found that rapamycin plus dasatinib showed greater inhibition on cell proliferation and clonogenic survival than either single agent. Such combination effects were additive in PC-3 and synergistic in DU145 cells, respectively, as reflected by combination index calculation. In addition, cell migration was suppressed to a greater extent by combination treatment than either treatment alone. At the molecular level, co-targeting mTOR and SFKs leads to strong inhibition of not only phosphorylation of these two proteins but also their downstream components such as Akt, focal adhesion kinase (FAK), S6K and 4E-BP1. These data indicate that co-targeting mTOR and Src pathways is able to achieve enhanced tumor-suppressing effects in prostate cancer cells with overexpression of both kinases, suggesting that this combinative intervention modality may serve as a potential anticancer strategy that could be further tested in advanced prostate cancer models in vivo. Note: This abstract was not presented at the conference. Citation Format: Yao Dai, Dietmar W Siemann. Combined inhibition of mTOR and Src family kinases enhances treatment effects in prostate cancer cells [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr B02.