https://scholars.lib.ntu.edu.tw/handle/123456789/586048
標題: | Vorinostat combined with brigatinib overcomes acquired resistance in EGFR-C797S-mutated lung cancer | 作者: | Lin, Chia-Yi Huang, Kuo-Yen Lin, Yi-Chun Yang, Shuenn-Chen Chung, Wei-Chia YIH-LEONG CHANG JIN-YUAN SHIH CHAO-CHI HO Lin, Chih-An Shih, Chih-Chun Chang, Ya-Hsuan Kao, Shih-Han PAN-CHYR YANG |
關鍵字: | Brigatinib; Combinational therapy; EGFR C797S; Lung cancer; STUB1 | 公開日期: | 2021 | 卷: | 508 | 來源出版物: | Cancer letters | 摘要: | The development of a new generation of tyrosine kinase inhibitors (TKIs) has improved the treatment response in lung adenocarcinomas. However, acquired resistance often occurs due to new epidermal growth factor receptor (EGFR) mutations. In particular, the C797S mutation confers drug resistance to T790M-targeting EGFR TKIs. To address C797S resistance, a promising therapeutic avenue is combination therapy that targets both total EGFR and acquired mutations to increase drug efficacy. We showed that combining vorinostat, a histone deacetylase inhibitor (HDACi), with brigatinib, a TKI, enhanced antitumor effects in primary culture and cell lines of lung adenocarcinomas harboring EGFR L858R/T790M/C797S mutations (EGFR-3M). While EGFR phosphorylation was decreased by brigatinib, vorinostat reduced total EGFR-3M (L858R/T790M/C797S) proteins through STUB1-mediated ubiquitination and degradation. STUB1 preferably ubiquitinated other EGFR mutants and facilitated protein turnover compared to EGFR-WT. The association between EGFR and STUB1 required the functional chaperone-binding domain of STUB1 and was further enhanced by vorinostat. Finally, STUB1 levels modulated EGFR downstream functions. Low STUB1 expression was associated with significantly poorer overall survival than high STUB1 expression in patients harboring mutant EGFR. Vorinostat combined with brigatinib significantly improved EGFR-TKI sensitivity to EGFR C797S by inducing EGFR-dependent cell death and may be a promising therapy in treating C797S-resistant lung adenocarcinomas. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/586048 | ISSN: | 03043835 | DOI: | 10.1016/j.canlet.2021.03.022 | SDG/關鍵字: | antineoplastic agent; brigatinib; EGFR protein, human; epidermal growth factor receptor; organophosphorus compound; pyrimidine derivative; vorinostat; animal; Bagg albino mouse; drug potentiation; drug resistance; drug screening; enzymology; genetics; HEK |
顯示於: | 醫學系 |
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