Targeting Hsp90 with FS-108 circumvents gefitinib resistance in EGFR mutant non-small cell lung cancer cells
Authors: Mei-Yu Geng
Min Zheng
Bing Xiong
Ai-Jun Shen
Xin Wang
Yue-Qin Wang
Jing-Ya Sun
Jian Ding
Dan-Qi Chen
Hong-Chun Liu
Min-Min Zhang
Jing-Kang Shen
Journal: Acta Pharmacologica Sinica (2016)
Discipline: PHARMACOLOGY & TOXICOLOGY
Keywords: Heat shock protein; Hsp90 inhibitor; gefitinib resistance; EGFR mutant; non-small cell lung cancer
Affiliations: Department of New Drug Screening Center, China Pharmaceutical University, Nanjing 210009, China., Division of Anti-tumor Pharmacology, Shanghai 201203, China., Synthetic Organic and Medicinal Chemistry Laboratory, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China., 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. 

Retracted: No

PubPeer comments:
 Possible image overlap in Figure 5D. *** ![file] , 
 There is another potential overlap in the upper row of Fig 5D: ![file] , 
 Correction, Published: 21 February 2020 It just came to the authoru2019s attention that three errors were introduced into the paper during the stage of figure preparation. Specifically, the Western blotting bands of GAPDH in Fig. 2b as well as Fig. 3b, cv PARP in HCC827 GR6 cells (Fig. 3b) and IHC staining images of EGFR and Hsp70 in group gefitinib 50u2009mg kg (Fig. 5d) were found to be misplaced inadvertently. These errors were made completely by accident. Under no circumstance did the authors falsify or u201cmake upu201d data in order to mislead the reviewers or readers. These corrections do not affect the scientific conclusions of each section and the entire paper. Nonetheless, the authors sincerely apologize for any inconvenience this might have caused. The corrected figure panels of Fig. 2b, 3b and 5d are presented as follows: *** **Fig. 2b** ![file] *** **Fig. 3b** ![file] *** **Fig. 5d** ![file] ,