Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Important cytogenetic and genetic risk factors for the development of UM include chromosome 3 monosomy, mutations in the guanine nucleotide-binding proteins GNAQ/GNA11, and loss of the BRACA1-associated protein 1 (BAP 1). Most primary UMs are treated conservatively with radiotherapy, but enucleation is necessary for large tumours. Despite the effectiveness of local control, up to 50% of UM patients develop metastasis for which there are no effective therapies.Attempts to utilize the targeted therapies that have been developed for the treatment of other cancers, including a range of signal transduction pathway inhibitors, have rarely produced significant outcomes in UM. Similarly, the application of immunotherapies that are effective in cutaneous melanoma to treat UM have also been disappointing. Other approaches that have been initiated involve proteasomal inhibitors and histone deacetylase inhibitors that are approved for the treatment of other cancers. Nevertheless, there have been occasional positive outcomes from these treatments in UM. Moreover, combination approaches in UM have also yielded some positive developments. It would be valuable to identify how to apply such therapies efficiently in UM, potentially via individualized tumour profiling. It would also be important to characterize UM tumours to differentiate the potential drivers of progression from those in other types of cancers.The recent identification of novel kinases and metastatic genes in UM tumours makes the development of new UM-specific treatments feasible. Accepted ArticleThis article is protected by copyright. All rights reserved A) Uveal Melanoma: Background and risk factors Uveal melanoma (UM) is the most common primary intraocular malignancy in adults and represents ~5 % of melanoma diagnoses in the US annually [1-3]. UM originates from ocular melanocytes with 85% of cases arising from the choroid region and the remainder from the ciliary body and iris [4]. The prognosis in UM is poor, in particular because around 50% of patients develop metastatic disease. Hepatic metastases occur in up to 90% of individuals, followed by metastases in lung and bones, and after establishment of metastatic disease the median survival time is only 4-5 months [5]. At the time of diagnosis, systemic metastases are reported in only 3%of patients, but it is likely that micro-metastases have already developed in many cases [6,7].Currently there are no effective systemic drug therapies for primary or metastatic UM [8,9].The median age at diagnosis is 62 years and the incidence of UM in males and females, and whether there is right or left eye involvement, is similar [10]. Underlying risk factors for UM include melanocytosis, melanocytoma, neurofibromatosis and the presence of atypical nevi [11][12][13][14]. Race is also a significant risk factor with a 150-fold greater incidence in fair-skinned over dark-skinned populations [15]. The incidence of UM in European countries varies wi...

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Although uveal melanoma (UM) is rare, it is the principal type of intraocular malignancy. Up to 50% of UM patients develop metastatic disease with low chances of survival beyond 18 months. At present there are no drugs that are effective in the treatment of primary or metastatic disease. We recently tested the hypothesis that the ErbB receptor family member HER2 may be a novel drug target in UM. We found that afatinib, which targets several ErbB receptors, including HER2, has potent anti-cancer and anti-metastatic actions in UM. The present study was undertaken to further evaluate the potential value of HER2 targeting in UM using the multi-kinase inhibitor lapatinib, that is currently approved for the treatment of HER2-positive cancers in patients. The anti-UM actions of lapatinib were assessed using cell viability, cell death and cell cycle analysis, and its anti-metastatic actions were evaluated using would healing and colony formation assays. Immunoblotting was used to substantiate the actions of lapatinib on apoptotic and HER2 signaling. The anti-UM actions of lapatinib were further evaluated in vivo in a UM xenograft mouse model. Lapatinib decreased the viability of four UM cell lines (IC50 values in MTT reduction assays were 3.67-6.53 µM). The antiproliferative activity of lapatinib was corroborated in UM cells isolated from patient tumors. In UM cell lines lapatinib promoted apoptosis and cell cycle arrest, and strongly inhibited cell migration and reproductive cell growth. Lapatinib dysregulated HER2-AKT/ERK/PI3K signalling in UM cell lines, as indicated by increased STAT1 expression, decreased expression of BCL-xL and cyclin D1, and decreased Bcl-xL:Bax ratio, which is consistent with enhanced apoptosis. Importantly, lapatinib and suppressed tumourigenesis in vivo in mice carrying UM cell xenografts. Together the present findings are consistent with the assertion that HER2 is a viable therapeutic target in UM. Lapatinib was active in primary and metastatic UM and is a clinically approved HER2 inhibitor. The activity of lapatinib in UM patients could now be evaluated directly in clinical trials.