Abstract 1998: Novel interplay between TANK-binding kinase (TBK1) and Yes-associated protein (YAP1) in KRAS mutant NSCLC

• Published in: Cancer research (Chicago, Ill.) Ill.), 2018-07, Vol.78 (13_Supplement), p.1998-1998
• Main Authors: Saha, Biswarup, Jaiswal, Neha, Bora-Singhal, Namrata, Chellappan, Srikumar
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2018-1998

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality in the United States. Lung adenocarcinomas are highly correlated with smoking and are characterized by mutations in KRAS, EGFR, BRAF and other oncogenes. Among them, KRAS mutations are widespread in adenocarcinomas in smokers and known to be a key player in various downstream signaling pathways contributing to genesis and progression of these tumors. More recently, the non-canonical IκB kinase, Tank Binding Kinase 1 (TBK1), has been found to facilitate tumorigenesis in KRAS mutant cancers. TBK1 has well documented functions in immune response, cell survival as well as in mitosis. While it has been suggested that TBK1-mediated regulation of Akt signaling might facilitate oncogenesis, the molecular mechanisms underlying TBK1 function downstream of KRAS is not fully elucidated. In a similar vein, Yes associated protein 1 (YAP1), the oncogenic component of the Hippo signaling cascade has been found to promote KRAS mediated oncogenesis and could substitute for the loss of Kras in mouse models of pancreatic cancer. In the present study, we have demonstrated a unique and novel molecular interplay between TBK1 and the oncogenic components of Hippo effector molecules, YAP1/TAZ. YAP1 and its ortholog, TAZ are known to be transcriptional co-activators, function to maintain organ size but often get activated in various types of cancer. We find that TBK1 physically interacts with YAP1, and knock-down (KD) or knocking-out (KO) of TBK1 resulted in a significant elevation of YAP1/TAZ expressions at protein level. We have tested four different KRAS and EGFR mutant NSCLC cell-lines; interestingly, the upregulation of YAP1 upon depletion of TBK1 was only restricted to the KRAS mutant cell-lines. Further, depletion of TBK1 led to the enrichment of YAP1 in the nucleus; notably, there were only minimal changes in the levels of MST1/2 and LATS, raising the possibility that these changes occur independent of the classic hippo signaling pathway. Depletion of TBK1 also resulted in the induction of EMT-like features in these cells, and increased the proportion of stem-like side-population. Mechanistically, TBK1 physically interacts with YAP1 in the cultured cells, and could phosphorylate it in vitro, on T110, T114, S128 and S131 residues. The underlying molecular mechanism(s) by which TBK1 regulates YAP1 expression are under investigation, and we hypothesize that this regulatory event is exclusive to