Abstract 3914: mTOR pathway components dictate cell response to Src inhibitors in prostate cancer cells

Abstract

Abstract Src inhibitors have been actively evaluated in the clinic for the treatment of advanced prostate cancer however the effects are modest. One interpretation is that oncogenic signaling pathways are redundant and blocking one pathway is not sufficient to yield considerable efficacies. mTOR pathway is commonly hyperactivated in prostate cancer. However, the functional role of mTOR in Src inhibitor-mediated response remains largely unknown. In the current study, we combined mTOR inhibitor rapamycin and Src inhibitor dasatinib to detect functional behaviors in prostate cancer cells. Cell proliferation and clonogenic survival were detected by MTT and colony formation assay, respectively. Wound-healing” scratch assay was conducted to monitor cell migration, and Matrigel-based transwell assay was applied to assess cell invasion. Protein expression was detected by Western blotting. Gene silencing was detected by siRNA transfection. We found that two agents combined together showed greater inhibition on proliferation and clonogenic survival than either agent alone. Such combination effects were additive or synergistic depending on the cell types, as reflected by combination index calculation. In addition, cell migration and invasion were inhibited in a greater extent by rapamycin plus dasatinib, compared to either treatment alone. At the molecular level, co-targeting mTOR and Src lead to clear inhibition of Src and its downstream pathway focal adhesion kinase (FAK), Akt and mTOR downstream components S6RP and 4E-BP1. Interestingly, knockdown 4EBP1, but not S6RP, attenuated dasatinib-mediated functional inhibition. These data indicate that adding mTOR inhibitors to Src-based intervention may achieve better treatment outcomes. Such combination could be evaluated as a novel treatment strategy for prostate cancer patients who are less responsive to Src inhibitors. In addition, 4EBP1 may be used as a candidate predictive biomarker for monitoring clinical effectiveness of Src inhibitors in prostate cancer. Citation Format: Yao Dai, Dietmar W. Siemann. mTOR pathway components dictate cell response to Src inhibitors in prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3914.