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Brigatinib, a newly discovered AXL inhibitor, suppresses AXL-mediated acquired resistance to osimertinib in EGFR-mutated non-small cell lung cancer.

Authors :
Han R
Lu CH
Hu C
Dou YY
Kang J
Lin CY
Wu D
Jiang WL
Yin GQ
He Y
Source :
Acta pharmacologica Sinica [Acta Pharmacol Sin] 2024 Jun; Vol. 45 (6), pp. 1264-1275. Date of Electronic Publication: 2024 Mar 04.
Publication Year :
2024

Abstract

In addition to the classical resistance mechanisms, receptor tyrosine-protein kinase AXL is a main mechanism of resistance to third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) osimertinib in EGFR-mutated non-small cell lung cancer (NSCLC). Developing an effective AXL inhibitor is important to sensitize osimertinib in clinical application. In this study we assessed the efficacy of brigatinib, a second-generation of anaplastic lymphoma kinase (ALK)-TKI, as a novel AXL inhibitor, in overcoming acquired resistance to osimertinib induced by AXL activation. We established an AXL-overexpression NSCLC cell line and conducted high-throughput screening of a small molecule chemical library containing 510 anti-tumor drugs. We found that brigatinib potently inhibited AXL expression, and that brigatinib (0.5 μM) significantly enhanced the anti-tumor efficacy of osimertinib (1 μM) in AXL-mediated osimertinib-resistant NSCLC cell lines in vitro. We demonstrated that brigatinib had a potential ability to bind AXL kinase protein and further inhibit its downstream pathways in NSCLC cell lines. Furthermore, we revealed that brigatinib might decrease AXL expression through increasing K48-linked ubiquitination of AXL and promoting AXL degradation in HCC827OR cells and PC-9OR cells. In AXL-high expression osimertinib-resistant PC-9OR and HCC827OR cells derived xenograft mouse models, administration of osimertinib (10 mg·kg <superscript>-1</superscript> ·d <superscript>-1</superscript> ) alone for 3 weeks had no effect, and administration of brigatinib (25 mg·kg <superscript>-1</superscript> ·d <superscript>-1</superscript> ) alone caused a minor inhibition on the tumor growth; whereas combination of osimertinib and brigatinib caused marked tumor shrinkages. We concluded that brigatinib may be a promising clinical strategy for enhancing osimertinib efficacy in AXL-mediated osimertinib-resistant NSCLC patients.<br /> (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Details

Language :
English
ISSN :
1745-7254
Volume :
45
Issue :
6
Database :
MEDLINE
Journal :
Acta pharmacologica Sinica
Publication Type :
Academic Journal
Accession number :
38438582
Full Text :
https://doi.org/10.1038/s41401-024-01237-4