Yue-Qin Wang1, Ai-Jun Shen2, Jing-Ya Sun2, Xin Wang2, Hong-Chun Liu2, Min-Min Zhang2, Dan-Qi Chen3, Bing Xiong3, Jing-Kang Shen3, Mei-Yu Geng2, Min Zheng4, Jian Ding2. 1. Department of New Drug Screening Center, China Pharmaceutical University, Nanjing 210009, China. 2. Division of Anti-tumor Pharmacology, Shanghai 201203, China. 3. Synthetic Organic and Medicinal Chemistry Laboratory, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. 4. Department of Thoracic Surgery, Shanghai Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China.
Abstract
AIM: Inhibition of heat shock protein (Hsp90) has been proven to be effective in overriding primary and acquired resistance of kinase inhibitors. In this study, we investigated the role of FS-108, a newly developed Hsp90 inhibitor, to overcome gefitinib resistance in EGFR mutant non-small cell lung cancer cells. METHODS: Cell proliferation was assessed using the SRB assay. Cell cycle distribution and apoptosis were analyzed by flow cytometry. Protein expression was examined by Western blotting. The in vivo effectiveness of FS-108 was determined in an NCI-H1975 subcutaneous xenograft model. RESULTS: FS-108 triggered obvious growth inhibition in gefitinib-resistant HCC827/GR6, NCI-H1650 and NCI-H1975 cells through inducing G2/M phase arrest and apoptosis. FS-108 treatment resulted in a remarkable degradation of key client proteins involved in gefitinib resistance and further abrogated their downstream signaling pathways. Interestingly, FS-108 alone exerted an identical or superior effect on circumventing gefitinib resistance compared to combined kinase inhibition. Finally, the ability of FS-108 to overcome gefitinib resistance in vivo was validated in an NCI-H1975 xenograft model. CONCLUSION: FS-108 is a powerful agent that impacts the survival of gefitinib-resistant cells in vitro and in vivo through targeting Hsp90.
AIM: Inhibition of heat shock protein (Hsp90) has been proven to be effective in overriding primary and acquired resistance of kinase inhibitors. In this study, we investigated the role of FS-108, a newly developed Hsp90 inhibitor, to overcome gefitinib resistance in EGFR mutant non-small cell lung cancer cells. METHODS: Cell proliferation was assessed using the SRB assay. Cell cycle distribution and apoptosis were analyzed by flow cytometry. Protein expression was examined by Western blotting. The in vivo effectiveness of FS-108 was determined in an NCI-H1975 subcutaneous xenograft model. RESULTS:FS-108 triggered obvious growth inhibition in gefitinib-resistant HCC827/GR6, NCI-H1650 and NCI-H1975 cells through inducing G2/M phase arrest and apoptosis. FS-108 treatment resulted in a remarkable degradation of key client proteins involved in gefitinib resistance and further abrogated their downstream signaling pathways. Interestingly, FS-108 alone exerted an identical or superior effect on circumventing gefitinib resistance compared to combined kinase inhibition. Finally, the ability of FS-108 to overcome gefitinib resistance in vivo was validated in an NCI-H1975 xenograft model. CONCLUSION:FS-108 is a powerful agent that impacts the survival of gefitinib-resistant cells in vitro and in vivo through targeting Hsp90.
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Authors: Darren A E Cross; Susan E Ashton; Serban Ghiorghiu; Cath Eberlein; Caroline A Nebhan; Paula J Spitzler; Jonathon P Orme; M Raymond V Finlay; Richard A Ward; Martine J Mellor; Gareth Hughes; Amar Rahi; Vivien N Jacobs; Monica Red Brewer; Eiki Ichihara; Jing Sun; Hailing Jin; Peter Ballard; Katherine Al-Kadhimi; Rachel Rowlinson; Teresa Klinowska; Graham H P Richmond; Mireille Cantarini; Dong-Wan Kim; Malcolm R Ranson; William Pao Journal: Cancer Discov Date: 2014-06-03 Impact factor: 39.397