Lapatinib dysregulates HER2 signaling and impairs the viability of human uveal melanoma cells

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.