Uveal melanoma (UM) is the principal type of intraocular malignancy in adults.Up to 50% of UM patients develop metastatic disease with very poor survival.There are few drugs available to treat the primary or metastatic UM.This study was undertaken to evaluate the anti-cancer effect of lapatinib and corroborate the potential of HER2 inhibition in the treatment of UM.The anti-UM activity of lapatinib was assessed using cell viability, cell death and cell cycle analysis, and its anti-metastatic actions were evaluated using would healing, invasion and colony formation assays.Immunoblotting was used to substantiate the actions of lapatinib on apoptotic and HER2 signaling.The anti-UM activity of lapatinib was further evaluated in a UM xenograft mouse model.Lapatinib decreased the viability of four UM cell lines (IC50: 3.67-6.53µM).The antiproliferative activity of lapatinib was corroborated in three primary cell lines isolated from UM patient tumors.In UM cell lines, lapatinib promoted apoptosis and cell cycle arrest, and strongly inhibited cell migration, invasion and reproductive cell growth.Lapatinib dysregulated HER2-AKT/ERK/PI3K signalling leading to the altered expression of apoptotic factors and cell cycle mediators in UM cell lines.Importantly, lapatinib suppressed tumourigenesis 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 is active in primary and metastatic UM as a clinically approved HER2 inhibitor.The activity of lapatinib in UM patients could be evaluated in future clinical trials.
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 utilise 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 which 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 individualised tumour profiling. It would also be important to characterise 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.
Abstract 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.
Autophagy is a form of programmed cell degradation that enables the maintenance of homeostasis in response to extracellular stress stimuli. Autophagy is primarily activated by starvation and mediates the degradation, removal, or recycling of cell cytoplasm, organelles, and intracellular components in eukaryotic cells. Autophagy is also involved in the pathogenesis of human diseases, including several cancers. Human uveal melanoma (UM) is the primary intraocular malignancy in adults and has an extremely poor prognosis; at present there are no effective therapies. Several studies have suggested that autophagy is important in UM. By understanding the mechanisms of activation of autophagy in UM it may be possible to develop biomarkers to provide more definitive disease prognoses and to identify potential drug targets for the development of new therapeutic strategies. This article reviews the current information regarding autophagy in UM that could facilitate biomarker and drug development.
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