Targeting histone deacetylase enhances the therapeutic effect of Erastin-induced ferroptosis in EGFR-activating mutant lung adenocarcinoma.

Zhang, Tuo; Sun, Beibei; Zhong, Chenxi; Xu, Ke; Wang, Zhexin; Hofman, Paul; Nagano, Tatsuya; Legras, Antoine; Breadner, Daniel; Ricciuti, Biagio; Divisi, Duilio; Schmid, Ralph A.; Peng, Ren-Wang; Yang, Haitang; Yao, Feng (2021). Targeting histone deacetylase enhances the therapeutic effect of Erastin-induced ferroptosis in EGFR-activating mutant lung adenocarcinoma. Translational lung cancer research, 10(4), pp. 1857-1872. AME Publishing 10.21037/tlcr-21-303

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Background

Intrinsic or acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is common, thus strategies for the management of EGFR-TKIs resistance are urgently required. Ferroptosis is a recently discovered form of cell death that has been implicated in tumorigenesis and resistance treatment. Accumulating evidence suggests that ferroptosis can be therapeutically exploited for the treatment of solid tumors; however, whether ferroptosis can be targeted to treat EGFR mutant lung cancer and/or overcome the resistance to EGFR-TKIs is still unknown.

Methods

The effect of ferroptosis inducers on a panel of EGFR mutant lung cancer cell lines, including those with EGFR-TKI intrinsic and acquired (generated by long-term exposure to the third-generation EGFR-TKI osimertinib), was determined using cytotoxicity assays. Further, drug candidates to enhance the effect of ferroptosis inducers were screened through implementing WGCNA (weighted gene co-expression network analysis) and CMAP (connectivity map) analysis. Flow cytometry-based apoptosis and lipid hydroperoxides measurement were used to evaluate the cell fates after treatment.

Results

Compared with EGFR-TKI-sensitive cells, those with intrinsic or acquired resistance to EGFR-TKI display high sensitivity to ferroptosis inducers. In addition, Vorinostat, a clinically used inhibitor targeting histone deacetylase, can robustly enhance the efficacy of ferroptosis inducers, leading to a dramatic increase of hydroperoxides in EGFR mutant lung cancer cells with intrinsic or acquired resistance to EGFR-TKI. Mechanistically, Vorinostat promotes ferroptosis via xCT downregulation.

Conclusions

Ferroptosis-inducing therapy shows promise in EGFR-activating mutant lung cancer cells that display intrinsic or acquired resistance to EGFR-TKI. Histone deacetylase inhibitor (HDACi) Vorinostat can further promote ferroptosis by inhibiting xCT expression.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Thoracic Surgery
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Forschungsbereich Mu50 > Forschungsgruppe Thoraxchirurgie

UniBE Contributor:

Schmid, Ralph; Peng, Ren-Wang and Yang, Haitang

Subjects:

600 Technology > 610 Medicine & health

ISSN:

2226-4477

Publisher:

AME Publishing

Language:

English

Submitter:

Thomas Michael Marti

Date Deposited:

27 Jul 2021 15:55

Last Modified:

27 Jul 2021 16:05

Publisher DOI:

10.21037/tlcr-21-303

PubMed ID:

34012798

Uncontrolled Keywords:

EGFR-mutant lung cancer ferroptosis histone deacetylase resistance

BORIS DOI:

10.48350/157715

URI:

https://boris.unibe.ch/id/eprint/157715

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