Abstract B157: YAP is a promising target in cutaneous melanoma

Abstract

Abstract The transcriptional regulator YAP (Yes-associated protein) has been implicated in tissue development and homeostasis and in cancer growth (Harvey et al. 2013). In uveal melanoma, YAP mediates oncogenic signaling of mutated G-proteins, driving tumor growth in a therapeutically exploitable manner (Yu et al. & Feng et al. 2014). The role of YAP in cutaneous melanoma (CM) is less well defined, although previous studies implicating YAP in metastasis and disease maintenance/progression (Nallet-Staub et al. 2014; Menzel et al. 2014), and encouraging data suggesting synergism between combination targeting of YAP and the Mitogen-Activated Protein Kinases (MAPK) pathway (Lin et al. 2015). Here we show that YAP is a critical mediator of disease maintenance and progression in some but not all CMs. In a primary CM we identified novel YAP mutations, which are rare in human cancer but are predicted to relieve YAP from inhibition by the Hippo pathway. By quantifying YAP expression by immunofluorescence, we found YAP was increased early in human melanocytic transformation, being elevated in nevi and in over 50% of primary CMs. Gene targeting of YAP with inducible shRNAs induced profound proliferative arrest and death in cultured CM cells (measured by MTT assay, EdU incorporation and propidium iodide staining respectively). The dependency on YAP of melanoma maintenance was validated in vivo using xenograft models of cell lines and of early passage patient-derived melanomas. Further, efficacy of YAP targeting synergized with MAPK inhibition in BRAF mutant CMs. However, some CMs were resistant to YAP targeting independent of BRAF/NRAS genotype and of levels of YAP protein expression or activation. These data compel the development of anti-YAP therapies in CM and the identification of biomarkers that predict response to YAP targeting. Citation Format: Jian zhong Tang, Xiaomeng Zhang, Ismael Vergara, Anthony Papenfuss, Kieran Harvey, Mark Shackleton. YAP is a promising target in cutaneous melanoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B157.