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Ann Tran, Ravi Doddapaneni, Wensi Tao, David T Tse, Daniel Pelaez; AZD4547 fibroblast growth factor receptor-1 inhibitor as a potential drug target for lacrimal gland adenoid cystic carcinoma. Invest. Ophthalmol. Vis. Sci. 2018;59(9):5609. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
We have identified Fibroblast growth factor receptor 1 (FGFR1) as an enriched biomarker in adenoid cystic carcinoma of the lacrimal gland (LGACC) following chemotherapeutic challenge through proteomic studies of paired patient samples. The aim of this study was to evaluate the anticancer activity of FGFR1-specific inhibition and cisplatin combination on established LGACC cell lines.
A total of 6 paired LGACC patient tissue samples (pre- and post-chemotherapy samples) were processed for proteomic analysis by an L-series array (Raybiotech) for 1,300 proteins. We then used established LGACC cell lines, and performed drug-screening studies using cisplatin, AZD4547, and the combination treatments. Growth curve analysis of LGACC cells at different intervals was measured by MTT assay. Migration of LGACC cells was examined by scratch assay. The apoptotic proportion of the LGACC cells was analyzed by TUNEL assay. The expression of proteins like cleaved caspase-3 and FGFR1was detected by western blot.
By proteomic analysis, we found that FGFR1 expression was upregulated in post-chemotherapy samples compared to controls. Cell growth curve analysis of LGACC cells demonstrated that the combination of AZD4547 and cisplatin significantly (p<0.02) inhibited the cell viability when compared to either agent alone. However, both AZD4547 or cisplatin exerted statistically significant effects as single agents when compared to controls. Migration assay confirmed the enhanced anti-metastatic potential of combination treatment with AZD4547 and cisplatin. By TUNEL assay, AZD4547 or cisplatin treatment groups induced apoptosis and found that the number of apoptotic cells was increased significantly (p<0.05) in the combination of AZD4547 and cisplatin. Further, western blot analysis revealed that AZD4547 and cisplatin treatment upregulates the cleavage of caspase-3 and downregulates the expression of FGFR1 compared to the other treatment groups.
Our findings demonstrate that AZD4547 potentiates the cytoreductive effects of cisplatin and suggest a potential therapeutic benefit of using AZD4547 in the adjuvant setting to cisplatin challenge for the management of LGACC patients.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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