The ERK signaling pathway returns to the limelight in uveal melanomas

Abstract

Uveal melanoma (UM), arising from melanocytes which reside in the uveal tract, is the most common primary intraocular tumor in adults. Despite successful treatment of the primary lesion by proton therapy or enucleation, up to 50% of UM patients develop metastases, predominantly in the liver. At present, there are no effective systemic treatments for metastatic UM, 80% of patients will die within 1 year after diagnosis of the metastases. Therefore, better understanding of the UM disease is urgently needed for successful development of effective therapies. UMs display a mutational status distinct from cutaneous melanoma types, having in 97.5% of the cases driver mutations in GNAQ or its paralogue GNA11 (GNAQ/11) that result in constitutive activation of the Gαq or Gα11 subunits, and less common mutations in CYSLTR2, and PLCβ4. Prior studies showed that oncogenic GNAQ/11 engages the PLCβPKC axis to stimulate the MAPK/ ERK signaling pathway (Chen et al., 2014). Downstream oncogenic GNAQ/11, a PLCβindependent TRIORhoAFAKYAP has been reported as another significant axis in UM cell progression (Feng et al., 2019). To characterize the intersection and importance of these different circuits downstream of oncogenic GNAQ/11, Chen and coworkers used a combination of pharmacologic and molecular genetic perturbations. In essence, the authors demonstrate that oncogenic GNAQ/11 stimulates the PLCβPKC axis, whose signal then branches into the MEKERK and FAKYAP pathways (Ma et al., 2021). It is worth noting that the authors also uncover differences in GNAQ/11 effects on these signaling that need to be further studied (Ma et al., 2021). Another twist in this study comes from the fact that genetic or pharmacological YAP inhibition has no significant effect on survival or colony formation ability of UM cells harboring oncogenic GNAQ/11 mutations (Ma et al., 2021), while FAK inhibition has only slight effects. Furthermore, YAP was mainly detected in the cytosol of the UM cells tested. These observations thereby indicate that the FAK/YAP element does not prevail in UM cell proliferation and survival. Supporting this conclusion analysis of the UM TCGA dataset did not point out to induction of YAP target genes, arguing against its active role in UM progression (Ma et al., 2021). Likewise, another recent study indicates that YAP activity is not associated with tumor sizes, metastatic status and the prognosis of UM patients (Kim et al., 2020). This is in contrast to mesothelioma cells, where YAP signaling is frequently activated and associated with poor prognosis (TCGA mesothelioma dataset) and which inhibition dramatically reduces mesothelioma cell survival (Kim et al., 2020). Hence, two recent reports show that YAP may have limited cellautonomous effect in UM cell proliferation and survival as compared to the MAPK/ERK signaling pathway. Nevertheless, a recent singlecell RNAseq study pointed out to a possible RHO/ RAC pathway activation in a subset of primary UM cells prone to metastasize (Pandiani et al., 2021). Combination of PKC and MEK inhibitors strongly reduced viability of mutant GNAQ/11 UM cell lines compared to combination of PKC and FAK inhibitors or FAK and MEK inhibitors (Ma et al., 2021). Compared to single drug formulations, only combination of PKC and MEK inhibitors have been reported to translate into meaningful antitumor responses, presumably due to feedbackmediated pathway reactivation in vivo (Chen et al., 2014). Furthermore, MEK inhibitors, in combination with dacarbazine looked promising in the phase 2, but not in the phase 3, clinical trial for UM patients (NCT01974752). Collectively, these findings strengthen the critical role of the PKCERK module in UM cell proliferation and survival. A phase Ib/II, multicenter study investigated the combined use of binimetinib (MEK inhibitor) and PKC inhibitor sotrastaurin (NCT01801358). However, this trial failed to show improvement in progressionfree survival of patients with UM. Another PKC inhibitor undergoes clinical trials in combination with binimetinib (NCT03947385). Given that the PKC family consists of three subgroups of enzymes (classical, novel, and atypical) with different requirement for diacylglycerol and calcium ion, one cannot rule out that effective therapeutic effect may be reached with drug combination targeting MEK and specific subsets of PKC such as the classical or novel isoforms. In keeping with this, in UM cells, MAPK activation has been shown to rely on classical and novel PKC.