Tankyrase Inhibition Represses Wnt Signaling And Lung Cancer Growth

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Despite progress in smoking cessation and advances in treatment, lung cancer remains the most common cause of cancer mortality for both men and women in the United States. This highlights a pressing need for new therapies. The Wnt signaling pathway is commonly deregulated in many types of cancer, including non-small cell lung cancer (NSCLC). Wnt pathway activation is reported in human lung adenocarcinoma and other lung cancer cell lines, as well as in disseminated lung cancers in patients, including those with KRAS and/or EGFR mutations (both common oncogenic events in NSCLC). Wnt pathway signaling is mechanistically linked to the metastatic potential of several cancers, including lung cancers. A pair of poly-ADP-ribose polymerase (PARP) enzymes, tankyrase (Tnks) 1 and Tnks2, have recently been highlighted as activating enzymes in the Wnt pathway. They do so by PARsylating and destabilizing Axin, a component of the adenomatous polyposis coli (APC)/axin/glycogen synthase kinase-3β (GSK-3β) complex that regulates Wnt signaling by destabilizing β-catenin. This study sought to evaluate the therapeutic potential of tankyrase inhibition in a transgenic cyclin E-driven mouse model of lung adenocarcinoma and its derived cancer cell lines, with confirmation in a panel of human lung cancer cell lines. The Wnt pathway was found to be deregulated in de novo murine and human lung cancers through candidate gene expression analysis by qPCR. For example, Wnt-inhibitory-factor 1 (Wif1) was found to be substantially repressed, in agreement with published work. Microarray analysis revealed that both Tnks1 and Tnks2 were upregulated in the lung cancers of the transgenic cyclin E mice, in comparison with both the adjacent normal and non-transgenic lung tissues. Tnks inhibitors XAV939 and IWR-1 Endo were growth inhibitory in a panel of murine and human NSCLC cell lines. Inhibition of Tnks by these compounds was accompanied by stabilization of axin and the tankyrase enzymes themselves, in agreement with previously reported data. Tnks-targeting compounds were also able to inhibit the expression of a stable Wnt-driven luciferase reporter in murine lung cancer cells. Specific genetic repression of Tnks1 or Tnks2 by siRNAs (versus control siRNAs) resulted in growth inhibition of murine lung cancer cell lines. Because Wnt pathway activity is known to be basally reduced in cultured cells in contrast to in vivo tumors, studies are underway to reintroduce Tnks-knockdown murine cancer cells into syngeneic host mice via tail vein injection, a model that recapitulates lung adenocarinoma in vivo. Successful completion of these studies will determine whether restoration of Wnt signaling control through inhibition of Tankyrase expression or activity can repress lung cancer growth. Reduced tumorigenesis would provide direct evidence for further development of Wnt and tankyrase-targeted therapies in lung and other cancers. 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 973. doi:1538-7445.AM2012-973