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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.
- 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.)
- Subjects :
- Animals
Female
Mice
Cell Line, Tumor
Indoles
Mice, Inbred BALB C
Mutation
Xenograft Model Antitumor Assays
Acrylamides pharmacology
Acrylamides therapeutic use
Aniline Compounds pharmacology
Aniline Compounds therapeutic use
Antineoplastic Agents pharmacology
Antineoplastic Agents therapeutic use
Axl Receptor Tyrosine Kinase
Carcinoma, Non-Small-Cell Lung drug therapy
Carcinoma, Non-Small-Cell Lung metabolism
Drug Resistance, Neoplasm drug effects
ErbB Receptors antagonists & inhibitors
ErbB Receptors metabolism
Lung Neoplasms drug therapy
Lung Neoplasms metabolism
Mice, Nude
Organophosphorus Compounds pharmacology
Organophosphorus Compounds therapeutic use
Protein Kinase Inhibitors pharmacology
Protein Kinase Inhibitors therapeutic use
Proto-Oncogene Proteins metabolism
Proto-Oncogene Proteins antagonists & inhibitors
Pyrimidines pharmacology
Pyrimidines therapeutic use
Receptor Protein-Tyrosine Kinases antagonists & inhibitors
Receptor Protein-Tyrosine Kinases metabolism
Subjects
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