Abstract A48: Tankyrase inhibitors impair directional cell migration of cancer cells by affecting microtubule dynamics and polarity signals
Authors: Barbara Lupo, Jorge Vialard, Andrea Bertotti, Letizia Lanzetti, Livio Trusolino
Journal: Clinical Cancer Research (2015)

Abstract Tumor colonization of distant sites underlies the vast majority of cancer-related deaths worldwide, despite current therapeutic efforts. Unfortunately, the emergence of metastasis-competent clones characterizes the rapid outgrowth of highly aggressive tumors, such as lung cancer [1]. Therefore, dissecting the molecular mechanisms that drive metastatic dissemination is the obligatory groundwork to discover novel therapeutic targets. In an endeavor to identify potential anti-invasive compounds, we performed a large-scale drug screen coupled to cell-based strategies, including wound healing and Transwell assays, in a panel of non-small cell lung cancer (NSCLC) cell lines. This approach led to the identification of two small molecules, namely XAV939 and JNJ928, both displaying remarkable inhibitory effects on cell invasiveness, in the absence of overt cytotoxicity. Both compounds are known to inhibit tankyrases 1&amp;2, two poly(ADP)-ribosylases that are gaining interest due to their involvement in cancer-related processes, ranging from wnt signaling to telomere maintenance and microtubule-based mitotic dynamics [2]. A scrutiny of polarity signaling pathways known to be involved in cell locomotion allowed us to allocate tankyrases within an accredited route governing directional cell migration that entails cdc42-dependent phosphorylation of GSK3β, the ensuing recruitment of APC to the plasma membrane, and the establishment of microtubule-dependent pulling forces that reorient the microtubule organizing center (MTOC) towards the leading edge [3]. Notably, all these spatially orchestrated events were compromised by tankyrase blockade, likely explaining the reduced chemotactic response of XAV939- and JNJ928-treated cells. Concurrently, tankyrase inhibition seemed to impinge on microtubule dynamics by stabilizing the microtubule network. Notably, dynamic instability of microtubules is needed for their “search and capture” function to generate an asymmetric microtubule array and facilitate cell movement [4]. Conceivably, suppression of dynamic instability by tankyrase blockade might prevent microtubules from probing outward, leading to reduced receptiveness of chemotactic inputs. Efforts are currently being placed to uncover the mechanistic details of such interconnections, which seem to adhere to the established notion that tankyrases bind to and regulate the activity of several microtubule-related proteins. Our results might add to the evolving landscape of tankyrases as drivers of many aspect of the transformed phenotype, holding promise for prospective – albeit still immature – employment of tankyrase inhibitors as anti-metastatic therapeutics in NSCLC. [1] D.X. Nguyen, P.D. Bos, J. Massagué, Metastasis: from dissemination to organ-specific colonization, Nat Rev Cancer 9 (2009) 274-284. [2] J.L. Riffell, C.J. Lord, A. Ashworth, Tankyrase-targeted therapeutics: expanding opportunities in the PARP family, Nat Rev Drug Discov 11 (2012) 923-936. [3] S. Etienne-Manneville, Polarity proteins in migration and invasion, Oncogene 27 (2008) 6970-6980. [4] S. Etienne-Manneville, Microtubules in cell migration, Annu Rev Cell Dev Biol 29 (2013) 471-499. Citation Format: Barbara Lupo, Jorge Vialard, Andrea Bertotti, Letizia Lanzetti, Livio Trusolino. Tankyrase inhibitors impair directional cell migration of cancer cells by affecting microtubule dynamics and polarity signals. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr A48.