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 therapy in treating C797S-resistant lung adenocarcinomas.

• Authors: Chia-Yi Lin, Kuo-Yen Huang, Yi-Chun Lin, Shuenn-Chen Yang, Wei-Chia Chung, Yih-Leong Chang, Jin-Yuan Shih, Chao-Chi Ho, Chih-An Lin, Chih-Chun Shih, Ya-Hsuan Chang, Shih-Han Kao, Pan-Chyr Yang
• Journal: Cancer letters (Cancer Lett) Vol. 508 Pg. 76-91 (06 28 2021) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 33775711 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

• Organophosphorus Compounds
• Pyrimidines
• Vorinostat
• EGFR protein, human
• ErbB Receptors
• brigatinib

Topics

• Adenocarcinoma of Lung (drug therapy, enzymology, genetics)
• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• Drug Synergism
• ErbB Receptors (genetics)
• HEK293 Cells
• Humans
• Lung Neoplasms (drug therapy, enzymology)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Mutation
• Organophosphorus Compounds (administration & dosage, pharmacology)
• Pyrimidines (administration & dosage, pharmacology)
• Random Allocation
• Vorinostat (administration & dosage, pharmacology)
• Xenograft Model Antitumor Assays