TBK1 mediated regulation of E2F1 as a therapeutic target in non-small cell lung cancer

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 DESCRIPTION (provided by applicant): TBK1 (Tank Binding Kinase 1) plays a major role in mediating innate immunity and is a known regulator of NF kB mediated transcriptional regulatory pathway. TBK1 activates survival pathways mediated by NFkB, and is an important downstream mediator of K-Ras-dependent oncogenic events. Recent studies have shown that the RalB signaling module and the exocyst complex activate TBK1 and promote survival of K-Ras mutant cancer cells through direct phosphorylation of Akt. Our earlier studies had shown that exposure of cells to nicotine, the addictive component of tobacco smoke, activates Akt and stabilizes XIAP, rendering non-small cell lung cancer (NSCLC) cells resistant to apoptosis induced by chemotherapeutic agents. This survival mechanism is also involved in induction of E2F1-mediated transcriptional activity, resulting in elevated expression of survivin. We had also found that nicotine could promote the growth and metastasis of NSCLC in mice, and could induce the expression of multiple matrix metalloproteinases including MMP9, MMP14 and MMP15 in an E2F1-dependent manner. A disruptor of the Rb-Raf-1 interaction, which inhibits the transcriptional activity of E2F1, could inhibit the expression of MMPs and prevent cell invasion, migration and metastasis in mice. Interestingly, our recent studies show that exposure of cells to nicotine activates TBK1 and facilitates nicotine-mediated cell proliferation. Levels of active phospho-TBK1 are elevated in human tumor samples as well as in tumors from mice that are exposed to nicotine. Further, TBK1 physically interacts with E2F1 transcription factor and phosphorylates it efficiently, enhancing E2F1-mediated transcription. TBK1 could also induce MMP promoters in an E2F1-dependent fashion, and depletion of TBK1 reduces the endogenous levels of MMP9 and 14. Based on these observations, we hypothesize that TBK1 is a vital downstream target of K-Ras as well as nicotinic acetylcholine receptor (nAChR)-mediated signaling and it facilitates the progression and metastasis of lung cancer through E2F1 regulation. Based on this hypothesis, we propose that the combination of small molecule inhibitors of TBK1 and E2F1 would be highly efficient in inhibiting the growth and metastasis of non-small cell lung cancers. We believe that these studies are highly innovative and will have a significant impact on our efforts to combat non-small cell lung cancer.