Abstract
Abstract
Purpose
Uveal melanoma (UM) is the most common intraocular malignancy in adults with a poor prognosis and a high recurrence rate. Currently there is no effective treatment for UM. Multi-kinase inhibitors targeting dysregulated pro-tumorigenic signalling pathways have revolutionised anti-cancer treatment but, as yet, their efficacy in UM has not been established. Here, we identified the multi-kinase inhibitor afatinib as a highly effective agent that exerts anti-UM effects in in vitro, ex vivo and in vivo models.
Methods
We assessed the anti-cancer effects of afatinib using cell viability, cell death and cell cycle assays in in vitro and ex vivo UM models. The signaling pathways involved in the anti-UM effects of afatinib were evaluated by Western blotting. The in vivo activity of afatinib was evaluated in UM xenograft models using tumour mass measurement, PET scan, immunohistochemical staining and TUNEL assays.
Results
We found that afatinib reduced cell viability and activated apoptosis and cell cycle arrest in multiple established UM cell lines and in patient tumour-derived primary cell lines. Afatinib impaired cell migration and enhanced reproductive death in these UM cell models. Afatinib-induced cell death was accompanied by activation of STAT1 expression and downregulation of Bcl-xL and cyclin D1 expression, which control cell survival and cell cycle progression. Afatinib attenuated HER2-AKT/ERK/PI3K signalling in UM cell lines. Consistent with these observations, we found that afatinib suppressed tumour growth in UM xenografted mice.
Conclusion
Our data indicate that afatinib activates UM cell death and targets the HER2-mediated cascade, which modulates STAT1-Bcl-xL/cyclin D1 signalling. Thus, targeting HER2 with agents like afatinib may be a novel therapeutic strategy to treat UM and to prevent metastasis.
Funder
Government of Jiangsu Province
Wuxi Municipal Bureau on Science and Technology
Ophthalmic Research Institute of Australia
University of Sydney
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Oncology,Molecular Medicine,General Medicine
Reference68 articles.
1. K.M. Egan, J.M. Seddon, R.J. Glynn, E.S. Gragoudas, D.M. Albert, Epidemiologic aspects of uveal melanoma. Surv. Ophthalmol. 32, 239–251 (1988)
2. A.D. Singh, L. Bergman, S. Seregard, Uveal melanoma: epidemiologic aspects. Ophthalmol. Clin. N. Am. 18, 75-84, viii (2005)
3. S. Rajpal, R. Moore, C.P. Karakousis, Survival in metastatic ocular melanoma. Cancer 52, 334–336 (1983)
4. S. Gupta, A.Y. Bedikian, J. Ahrar, J. Ensor, K. Ahrar, D.C. Madoff, M.J. Wallace, R. Murthy, A. Tam, P. Hwu, Hepatic artery chemoembolization in patients with ocular melanoma metastatic to the liver: Response, survival, and prognostic factors. Am. J. Clin. Oncol. 33, 474–480 (2010)
5. S.W. Ryu, R. Saw, R.A. Scolyer, M. Crawford, J.F. Thompson, C. Sandroussi, Liver resection for metastatic melanoma: Equivalent survival for cutaneous and ocular primaries. J. Surg. Oncol. 108, 129–135 (2013)
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