Vorinostat combined with brigatinib overcomes acquired resistance in EGFR-C797S-mutated lung cancer
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…
Read the paper
Related studies
- Combining in silico and in vitro approaches to identification of potent inhibitor against phospholipase A2 (PLA2)
- In silico and in vitro studies: investigating the chemical composition, DFT, molecular docking, and dynamic simulation of Satureja candidissima (Munby) Briq essential oil as a potential antibacterial agent
- Quercetin combined with ciprofloxacin and gentamicin inhibits biofilm formation and virulence in Staphylococcus aureus
- In silico study of the mechanism of action, pharmacokinetic and toxicological properties of some N-methylanthranilates and their analogs
- Anticonvulsant Effects of Citronellal, Daidzin, and Phytol, Possibly Through GABAA Receptor and Voltage-Gated Sodium Channel Interaction Pathways: In Vivo and In Silico Studies
- 2-Phenylcyclopropylmethylamine (PCPMA) Derivatives as D3R-Selective Ligands for 3D-QSAR, Docking and Molecular Dynamics Simulation Studies
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.