br Ethical standards br Conflicts

Ethical standards
Conflicts of interest
Funding This study was funded by the National Natural Science Foundation of China (grant numbers 81560146, 81660148 and 81760151), Gansu Province health industry research project (grant number GSWSKY-2015-10) and Lanzhou Chengguan District Science and Technology Plan Project (grant number 2018SHFZ0068).
Significance
Introduction Recent advances in omics technologies have enabled the sequencing and characterization of cancers to an unprecedented depth, revealing mechanisms of growth and molecular drivers of disease. Bioinformatics analyses of these data have demonstrated a large heterogeneity in genetic drivers, highlighting complex biological networks toward the identification of therapeutic targets. These large-scale genomics efforts have revealed a small set of cancers that are driven by only a select number of mutational events. One such cancer, uveal melanoma (UM), is characterized by a gain-of-function l-name in the heterotrimeric G protein, Gαq. A hotspot mutation in GNAQ or in GNA11 results in encoding constitutively active Gαq proteins rendering them as driver oncogenes in approximately 93% of UM (Van Raamsdonk et al., 2009, Van Raamsdonk et al., 2010). Another ∼4% of UM harbor activating mutations in CYSLTR2, a Gαq-linked G protein-coupled receptor (GPCR) (Moore et al., 2016), firmly establishing UM as a Gαq-driven malignancy. Aberrant activity of G proteins and GPCRs have been frequently associated with an oncogenic state and promotion of tumorigenesis (Dorsam and Gutkind, 2007, O'Hayre et al., 2013). However, the precise molecular mechanisms by which prolonged Gαq signaling controls cancer cell growth are still under investigation. We and others have previously shown that these mechanisms are in part due to unique signaling circuitries that lead to the activation of YAP, a transcriptional co-activator regulated by the Hippo pathway. In turn, YAP activation is necessary for UM growth (Feng et al., 2014b, Yu et al., 2014a). As a key downstream target of the tumor suppressive Hippo signaling cascade, YAP is over-activated in multiple cancers (Moroishi et al., 2015, Yu et al., 2015). Despite this, pharmacological targeting of YAP or the Hippo pathway has been challenging. Verteporfin, an ophthalmological drug, inhibits YAP-TEAD interaction, which is the major transcriptional factor regulated by YAP, in UM (Feng et al., 2014b, Yu et al., 2014a) with some anecdotal clinical success (Barbazetto et al., 2003, Soucek and Cihelkova, 2006). However, the potential for verteporfin as a therapeutic has been hindered by its high systemic toxicities after prolonged use (Arnold et al., 2004, Azab et al., 2004). Currently, no effective therapeutic targets are available for UM, and no specific YAP inhibitors are currently in clinical use (Moroishi et al., 2015). A more complete understanding of Hippo/YAP-regulating mechanisms in cancer could identify urgently needed therapeutic opportunities to inhibit YAP-dependent tumors, including UM.
Results
Discussion The transformative potential of Gαq signaling was established in the early 1990s (Gutkind et al., 1991, Kalinec et al., 1992); however, the precise signaling events by which Gαq and its linked receptors transduce sustained proliferative signals is not yet well defined. This is due in part to the large number of second-messenger generating systems and signaling events that can be perturbed upon Gαq activation. The activation of these second-messenger systems and their direct targets, including ion channels and kinases such as PKC, calcium/calmodulin-dependent protein kinases, and mitogen-activated protein kinase (MAPK), are responsible for most of the rapid physiological responses elicited by GPCRs (Griner and Kazanietz, 2007, Howe, 2011, Julius and Nathans, 2012, Newton, 2010, Prevarskaya et al., 2011, Rozengurt, 2007, Sassone-Corsi, 2012). Recent studies have identified additional members of this network for UM, highlighting the role of GEFs such as RasGRP3 in MAPK activation (Chen et al., 2017). Despite this link, therapeutic strategies targeting MAPKs have yet to be successful. Clinical trials demonstrated that MEK inhibition with selumetinib or trametinib, as single agents or in combination with dacarbazine, has little impact on the overall survival of UM patients (Carvajal et al., 2014, Carvajal et al., 2018). This suggests that, although MEK/MAPK networks activated by PLCβ may contribute to UM initiation, they may not be critical for the maintenance of tumorigenic potential in UM.