Abstract 1523: Novel role of TBK1 in breast cancer EMT

Abstract TANK Binding Kinase 1 (TBK1) regulates interferon signaling and NFκB function by acting as a non-canonical IκB kinase. TBK1 also participates in RalB-mediated inflammatory responses and is essential for the survival of non-small cell lung cancers (NSCLC) driven by oncogenic KRAS. Recent evidence suggests a role for TBK1 as a driver of cancer progression and it is overexpressed in breast, colon, lung and pancreatic cancers. Our published results demonstrate that TBK1 is essential for proper microtubule dynamics and regulation of mitosis. Here we show that knockdown of TBK1 results in a decreased expression of mesenchymal genes involved in EMT and a re-distribution of β-catenin in breast cancer cells. Similarly, expression of matrix metalloproteinases 2 and 9 was altered. This led us to hypothesize that TBK1 acts as an EMT driver in cancer. Inhibition of TBK1 resulted in decreased adherence dependent as well as independent colony formation and stem cell self-renewal, while inducing senescence like phenotypes. We propose that TBK1 mediated EMT is mediated through its interaction with the transcription factor E2F1; the interaction was detected in breast cancer cell lines as well as breast cancer Tissue Micro Arrays. To get a holistic view of the changes that take place in the cell after TBK1 knockdown, we performed a global metabolomics and RNAseq analysis of breast cancer cell lines. An integrated analysis of this data suggested significant alterations in glucose, galactose and nucleotide metabolism upon TBK1 knockdown. Two of the genes that were markedly altered were aldoketoreductase1 B10 (AKR1B10) and thymidine phosphorylase (TP); attention was focused on these genes, as both have been reported to be cancer drivers and their over-expression results in poor prognosis. We observed a downregulation of AKR1B10 and TP in response to the TBK1 knockdown. Experiments are under way to investigate whether the pro-cancer role of TBK1 is dependent on AKR1B10 and TP, especially in breast cancer cells. These results suggest that TBK1 mediated EMT might be a function of the altered expression of mesenchymal proteins and the metabolic profile of the cell brought about by TBK1. Citation Format: Meenu Maan, Mainak Dutta, Neha Jaiswal, Harold Saavedra, Srikumar Chellappan. Novel role of TBK1 in breast cancer EMT [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1523.