Targeting Hsp90 with FS-108 circumvents gefitinib resistance in EGFR mutant non-small cell lung cancer cells.
OBJECTIVE
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.


CONCLUSIONS
FS-108 is a powerful agent that impacts the survival of gefitinib-resistant cells in vitro and in vivo through targeting Hsp90.
Department of New Drug Screening Center, China Pharmaceutical University, Nanjing 210009, China.
Yue-Qin
YQ
Wang
Division of Anti-tumor Pharmacology, Shanghai 201203, China.
Ai-Jun
AJ
Shen
Division of Anti-tumor Pharmacology, Shanghai 201203, China.
Jing-Ya
JY
Sun
Division of Anti-tumor Pharmacology, Shanghai 201203, China.
Xin
X
Wang
Division of Anti-tumor Pharmacology, Shanghai 201203, China.
Hong-Chun
HC
Liu
Division of Anti-tumor Pharmacology, Shanghai 201203, China.
Min-Min
MM
Zhang
Synthetic Organic and Medicinal Chemistry Laboratory, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Dan-Qi
DQ
Chen
Synthetic Organic and Medicinal Chemistry Laboratory, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Bing
B
Xiong
Synthetic Organic and Medicinal Chemistry Laboratory, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Jing-Kang
JK
Shen
Division of Anti-tumor Pharmacology, Shanghai 201203, China.
Mei-Yu
MY
Geng
Department of Thoracic Surgery, Shanghai Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China.
Min
M
Zheng
Division of Anti-tumor Pharmacology, Shanghai 201203, China.
Jian
J
Ding
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D000077156:Gefitinib; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D064593:Heterografts; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology* / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation; D009368:Neoplasm Transplantation; D010080:Oxazoles / Q000494:pharmacology* / Q000627:therapeutic use; D011799:Quinazolines / Q000494:pharmacology*; D012118:Resorcinols / Q000494:pharmacology* / Q000627:therapeutic use
D000970:Antineoplastic Agents; C000613702:FS-108; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D010080:Oxazoles; D011799:Quinazolines; D012118:Resorcinols; D066246:ErbB Receptors; D000077156:Gefitinib