Lapatinib dysregulates HER2 signaling and impairs the viability of human uveal melanoma cells.
Wenying Shu, Janney Z Wang, Xue Zhu, Ke Wang, Svetlana Cherepanoff, R Max Conway, Michele C Madigan, Li-Anne Lim, Hong Zhu, Ling Zhu, Michael Murray, Fanfan Zhou
Author Information
Wenying Shu: The University of Sydney, Sydney Pharmacy School, Faculty of Medicine and Health NSW 2006, Australia.
Janney Z Wang: The University of Sydney, Sydney Pharmacy School, Faculty of Medicine and Health NSW 2006, Australia.
Xue Zhu: Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu Province 214063, China.
Ke Wang: Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu Province 214063, China.
Svetlana Cherepanoff: SydPath, Department of Anatomical Pathology, St Vincent's Hospital, Darlinghurst, NSW 2010, Australia.
R Max Conway: Ocular Oncology Unit, Sydney Eye Hospital and The Kinghorn Cancer Centre, Sydney, NSW 2006, Australia.
Michele C Madigan: Save Sight Institute, The University of Sydney, Sydney, NSW 2006, Australia.
Li-Anne Lim: Ocular Oncology Unit, Sydney Eye Hospital and The Kinghorn Cancer Centre, Sydney, NSW 2006, Australia.
Hong Zhu: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang Province 310058, China.
Ling Zhu: Save Sight Institute, The University of Sydney, Sydney, NSW 2006, Australia.
Michael Murray: The University of Sydney, Sydney Pharmacy School, Faculty of Medicine and Health NSW 2006, Australia.
Fanfan Zhou: The University of Sydney, Sydney Pharmacy School, Faculty of Medicine and Health NSW 2006, Australia.
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 (IC: 3.67-6.53 µM). 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.
