Full metadata record
DC Field | Value | Language |
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dc.contributor.author | 권영주 | * |
dc.contributor.author | 이윤실 | * |
dc.date.accessioned | 2022-11-03T16:31:10Z | - |
dc.date.available | 2022-11-03T16:31:10Z | - |
dc.date.issued | 2022 | * |
dc.identifier.issn | 2211-3428 | * |
dc.identifier.issn | 2211-3436 | * |
dc.identifier.other | OAK-32440 | * |
dc.identifier.uri | https://dspace.ewha.ac.kr/handle/2015.oak/262898 | - |
dc.description.abstract | Purpose Although epidermal growth factor receptor (EGFR)-activating mutations in non-small cell lung cancer (NSCLC) usually show sensitivity to first-generation EGFR-tyrosine kinase inhibitors (TKIs), most patients relapse because of drug resistance. Heat shock protein 27 (HSP27) has been reported to be involved in the resistance of EGFR-TKIs, although the underlying mechanism is unclear. Here, we explore the mechanisms of HSP27-mediated EGFR TKI resistance and propose novel therapeutic strategies. Methods To determine the mechanism of HSP27 associated gefitinib resistance, differences were assessed using gefitinib-sensitive and -resistant NSCLC cell lines. In vivo xenograft experiments were conducted to elucidate the combinatorial effects of J2, a small molecule HSP27 inhibitor, and gefitinib. Analyses of human NSCLC tissues and PDX tissues were also used for comparison of HSP27 and phosphorylated AKT expression. Results Large-scale cohort analysis of NSCLC cases revealed that HSP27 expression correlated well with the incidence of EGFR mutations and affected patient survival. Increased pAKT and HSP27 was observed in gefitinib-resistant cells compared with gefitinib-sensitive cells. Moreover, increased phosphorylation of HSP27 by gefitinib augmented its protein stability and potentiated its binding activity with pAKT, which resulted in increased gefitinib resistance. However, in gefitinib-sensitive cells, stronger binding activity between EGFR and HSP27 was observed. Moreover, these phenomena occurred regardless of EGFR mutation including secondary mutations, such as T790M. AKT knockdown switched HSP27-pAKT binding to HSP27-EGFR, which promoted gefitinib sensitivity in gefitinib-resistant cells. Functional inhibition of HSP27 yielded sensitization to gefitinib in gefitinib-resistant cells by inhibiting the interaction between HSP27 and pAKT. Conclusions Our results indicate that combination of EGFR-TKIs with HSP27 inhibitors may represent a good strategy to overcome resistance to EGFR-TKIs, especially in cancers exhibiting AKT pathway activation. | * |
dc.language | English | * |
dc.publisher | SPRINGER | * |
dc.subject | Non-small cell lung cancer (NSCLC) | * |
dc.subject | Heat shock protein 27 (HSP27) | * |
dc.subject | EGFR-TKI resistance | * |
dc.subject | AKT activation | * |
dc.title | Activation of the HSP27-AKT axis contributes to gefitinib resistance in non-small cell lung cancer cells independent of EGFR mutations | * |
dc.type | Article | * |
dc.relation.issue | 5 | * |
dc.relation.volume | 45 | * |
dc.relation.index | SCIE | * |
dc.relation.index | SCOPUS | * |
dc.relation.startpage | 913 | * |
dc.relation.lastpage | 930 | * |
dc.relation.journaltitle | CELLULAR ONCOLOGY | * |
dc.identifier.doi | 10.1007/s13402-022-00696-3 | * |
dc.identifier.wosid | WOS:000836529500002 | * |
dc.identifier.scopusid | 2-s2.0-85135486117 | * |
dc.author.google | Choi, Seul-Ki | * |
dc.author.google | Kim, Minsuh | * |
dc.author.google | Lee, Haeseung | * |
dc.author.google | Kwon, Youngjoo | * |
dc.author.google | Cha, Hyuk-Jin | * |
dc.author.google | Jang, Se Jin | * |
dc.author.google | Na, Younghwa | * |
dc.author.google | Lee, Yun-Sil | * |
dc.contributor.scopusid | 권영주(12446435600) | * |
dc.contributor.scopusid | 이윤실(17137192000) | * |
dc.date.modifydate | 20240422124907 | * |