Vorinostat combined with brigatinib overcomes acquired resistance in EGFR-C797S-mutated lung cancer
Journal
Cancer letters
Journal Volume
508
Date Issued
2021
Author(s)
Lin, Chia-Yi
Huang, Kuo-Yen
Lin, Yi-Chun
Yang, Shuenn-Chen
Chung, Wei-Chia
Lin, Chih-An
Shih, Chih-Chun
Chang, Ya-Hsuan
Kao, Shih-Han
Abstract
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.
Subjects
Brigatinib; Combinational therapy; EGFR C797S; Lung cancer; STUB1
Other Subjects
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
Type
journal article