Poster Presentation 29th Lorne Cancer Conference 2017

Exploring the role of the WNT-binding receptor tyrosine kinase RYK in cancer, with a focus on melanoma and lung squamous cell carcinoma (#259)

James P Roy 1 2 , Michael M Halford 1 2 , Steven A Stacker 1 2
  1. Tumour Angiogenesis and Microenvironment Program, Peter MacCallum Cancer Centre, Victorian Comprehensive Cancer Centre, Melbourne, VIC, Australia
  2. The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia

Receptor tyrosine kinases (RTKs) are a large family of cell-surface signalling molecules vital for many cellular processes including cell proliferation, migration and survival. Dysregulation of these receptors frequently leads to cancer development or maintenance; consequently RTKs have proven popular and successful drug targets. A wide variety of ligands signal through RTKs, with four understudied RTK subfamilies (RYK, ROR, PTK7 and MuSK) binding WNT ligands. WNTs are developmental morphogens whose aberrant signalling is a key driver of numerous cancers. While therapeutically targeting the WNTs directly has proven problematic, an alternative strategy aimed at targeting and blocking the WNT/WNT-receptor interactions has been more successful with resultant clinical trials (Blagodatski et al. 2014).

RYK is a WNT-binding member of the RTKs with an indispensible role in development commonly signalling non-canonical WNT pathways, especially upon WNT5A stimulation (Andre et al. 2012; Macheda et al. 2012). Despite this little is known about the role of RYK in both physiological adult cells and cancer. As WNT5A is becoming accepted as a pivotal player in many cancers (Asem et al. 2016), we hypothesise that RYK, functioning as a WNT-receptor, is important for cancer progression and consequently we can therapeutically target this RYK/WNT signalling.

Analyses of the literature and bioinformatic datasets presented melanoma and lung squamous cell carcinoma (SCC) as potential RYK-dependent cancers. RYK siRNA-knockdown reduced viability of melanoma and lung SCC cell lines. Consequently, these lines are being established as in vitro models to examine RYK signalling in cancer and allow the evaluation of two RYK signalling inhibitors developed by our lab. These inhibitors are a fully human monoclonal antibody to RYK inhibiting WNT binding and a ligand trap where the RYK extracellular region is fused to a human Fc region. After in vitro evaluation, these potential therapeutics will facilitate identification of further cancer cell lines requiring RYK for a key oncogenic process. Lastly, xenograft mouse models will be established allowing an in vivo examination of RYK oncogenic signalling as well as initial pre-clinical studies of the RYK inhibitors.

  1. Andre, P., Q. Wang, N. Wang, B. Gao, A. Schilit, M. M. Halford, S. A. Stacker, X. Zhang, and Y. Yang. 2012. 'The Wnt coreceptor Ryk regulates Wnt/planar cell polarity by modulating the degradation of the core planar cell polarity component Vangl2', Journal of Biological Chemistry, 287: 44518-25.
  2. Asem, M. S., S. Buechler, R. B. Wates, D. L. Miller, and M. S. Stack. 2016. 'Wnt5a Signaling in Cancer', Cancers, 8: 79.
  3. Blagodatski, A., D. Poteryaev, and V. L. Katanaev. 2014. 'Targeting the Wnt pathways for therapies', Mol Cell Ther, 2: 28.
  4. Macheda, M. L., W. W. Sun, K. Kugathasan, B. M. Hogan, N. I. Bower, M. M. Halford, Y. F. Zhang, B. E. Jacques, G. J. Lieschke, A. Dabdoub, and S. A. Stacker. 2012. 'The Wnt receptor Ryk plays a role in mammalian planar cell polarity signaling', Journal of Biological Chemistry, 287: 29312-23.