View : 535 Download: 0
Activation of the HSP27-AKT axis contributes to gefitinib resistance in non-small cell lung cancer cells independent of EGFR mutations
- Title
- Activation of the HSP27-AKT axis contributes to gefitinib resistance in non-small cell lung cancer cells independent of EGFR mutations
- Authors
- Choi, Seul-Ki; Kim, Minsuh; Lee, Haeseung; Kwon, Youngjoo; Cha, Hyuk-Jin; Jang, Se Jin; Na, Younghwa; Lee, Yun-Sil
- Ewha Authors
- 권영주; 이윤실
- SCOPUS Author ID
- 권영주; 이윤실
- Issue Date
- 2022
- Journal Title
- CELLULAR ONCOLOGY
- ISSN
- 2211-3428
2211-3436
- Citation
- CELLULAR ONCOLOGY vol. 45, no. 5, pp. 913 - 930
- Keywords
- Non-small cell lung cancer (NSCLC); Heat shock protein 27 (HSP27); EGFR-TKI resistance; AKT activation
- Publisher
- SPRINGER
- Indexed
- SCIE; SCOPUS
- Document Type
- Article
- 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.
- DOI
- 10.1007/s13402-022-00696-3
- Appears in Collections:
- 약학대학 > 약학과 > Journal papers
- Files in This Item:
There are no files associated with this item.
- Export
- RIS (EndNote)
- XLS (Excel)
- XML