Vorinostat combined with brigatinib overcomes acquired resistance in EGFR-C797S-mutated lung cancer. (28th June 2021)

• Record Type: Journal Article
• Authors: Lin, Chia-Yi; Huang, Kuo-Yen; Lin, Yi-Chun; Yang, Shuenn-Chen; Chung, Wei-Chia; Chang, Yih-Leong; Shih, Jin-Yuan; Ho, Chao-Chi; Lin, Chih-An; Shih, Chih-Chun; Chang, Ya-Hsuan; Kao, Shih-Han; Yang, Pan-Chyr
• Is Part Of: Cancer letters. Volume 508(2021)
• Page Start: 76
• Page End: 91
• Publication Date: 2021-06-28
• Subjects: Lung cancer -- EGFR C797S -- Brigatinib -- Combinational therapy -- STUB1; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2021.03.022
• Languages: English
• ISSNs: 0304-3835

Abstract

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. Highlights: Recent reports demonstrated that the C797S mutation confers drug resistance to T790M-targeting epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) in lung adenocarcinomas. New TKIs, including brigatinib, were repurposed for osimertinib-resistant lung adenocarcinoma with acceptable efficacy, but other combined therapies remain to be determined. Combination of vorinostat and brigatinib shows promising therapeutic value in C797S-resistant lung adenocarcinoma, as relapse of NSCLC highly depends on EGFR mutations, therefore providing an alternative off-label use of FDA-approved vorinostat and brigatinib.