ArticleActa pharmacologica Sinica2024
Brigatinib, a newly discovered AXL inhibitor, suppresses AXL-mediated acquired resistance to osimertinib in EGFR-mutated non-small cell lung cancer.
Article in Acta pharmacologica Sinica, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed, 18 citations in OpenAlex.
- Cancer drug response and resistance: molecular mechanisms and combating strategies.Signal transduction and targeted therapy · 2026Review
- AXL Inhibitors in Oncology Clinical Trials: A Review.Journal of immunotherapy and precision oncology · 2026Review
- [Role of Receptor Tyrosine Kinase AXL in Cancer Targeted Therapy Drug Resistance].Zhongguo fei ai za zhi = Chinese journal of lung cancer · 2026Review
- Nano-Enabled Fluorescence Switching: A Novel Strategy for PDGFRβ Detection and TKI Therapy Monitoring.Research (Washington, D.C.) · 2026Article
- Germ-line exon 21 EGFR V831H mutation in advanced NSCLC resistance to almonertinib: a case report.Frontiers in oncology · 2026Article
- ZDHHC11-mediated AXL palmitoylation promotes osimertinib resistance in non-small-cell lung cancer.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Anti-EGFR therapy can overcome acquired resistance to the third-generation ALK-tyrosine kinase inhibitor lorlatinib mediated by activation of EGFR.Acta pharmacologica Sinica · 2025Article
- Recent advances in TAM mechanisms in lung diseases.Journal of translational medicine · 2025Review
- The changing treatment landscape of EGFR-mutant non-small-cell lung cancer.Nature reviews. Clinical oncology · 2025Review
- AXL: shapers of tumor progression and immunosuppressive microenvironments.Molecular cancer · 2025Review
- Osimertinib acquired resistance among patients with EGFR-mutated NSCLC: from molecular mechanisms to clinical therapeutic strategies.Cancer drug resistance (Alhambra, Calif.) · 2025Review
- New advances in understanding the mechanisms and treatment challenges of ALK-targeted therapy resistance in lung cancer.Cancer drug resistance (Alhambra, Calif.) · 2025Review
- Kinase Inhibitors and Kinase-Targeted Cancer Therapies: Recent Advances and Future Perspectives.International journal of molecular sciences · 2024Review
- The Role of Axl Inhibition and Immune Checkpoint Blockade in Non-small Cell Lung Cancer: Current Understanding and Treatment Strategies.Cancer diagnosis & prognosisReview
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Authors and funding
10 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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
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