Abstract 1510: Blockade of the mTOR/NF-κB signaling axis augments prostate cancer treatment responses through suppression of a microenvironment-derived DNA damage secretory program

Abstract

Abstract Background/Rationale: Resistance to cytotoxic chemo- and radiotherapy is a common event in advanced prostate cancers. While resistance is established as a consequence of cancer cell intrinsic genetic and epigenetic changes, emerging evidence indicates that therapy failure is also caused by cell extrinsic factors such as cytokines, growth factors, proteases and other soluble ligands generated from damaged stromal cells in the tumor microenvironment (TMEN). We recently reported a unique feature of stromal cells, namely a DNA damage secretory phenotype (DDSP) resulting from genotoxic therapeutics. Thus, anti-cancer therapies that cause DNA damage responses (DDR), unexpectedly, trigger pro-survival signaling in neoplastic or pre-neoplastic cells and may promote subsequent therapy resistance. Results: In this study, we show that molecular inhibition of the mammalian target of rapamycin (mTOR) through genetic or chemical approaches suppresses a cellular secretory program resulting from exposure to genotoxic agents. We identified a physical association between mTOR and the I-kappa-B kinase (IKK) complex which is activated by DNA damage stimuli, and found IKKα to be the major subunit that directly interacts with mTOR while assembling the IKK complex. Rapamycin abrogates IKKα phosphorylation, IαBβ degradation and the central action-p65/p50 nuclear translocation. Thus, IKK catalytic subunits are not equally implicated in propagating damage signals to NF-κB, with IKKα playing the pivotal role. We determined that the mTOR/Raptor complex is activated by genotoxic stress and promotes NF-κB signaling. Suppressing mTOR dramatically abolished transcriptional levels of NF-κB target genes. We also determined that paracrine-acting DDSP factors are regulated through both transcriptional and post-transcriptional mechanisms, as upregulation of S6K and downregulation of 4E-BP1 play essential and synergistical roles in synthesis of DDSP factors. Finally, we determined that mTORC1 is the predominant mediator of the development of the DDSP phenotype, and it receives signals from upstream kinases. Interestingly, PI3K is not required for signal transduction of damage responses in prostate fibroblasts, which occurs through Akt phosphorylation caused by activated p38 MAPK signaling. Conclusions: These studies establish that mTOR is a novel target for therapeutic intervention in the mitigation of resistance mechanisms derived from the tumor microenvironment following genotoxic cancer treatments. These studies suggest that mTOR inhibitors may have efficacy in augmenting tumor responses to ionizing radiation and/or chemotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1510. doi:1538-7445.AM2012-1510