ArticleActa pharmacologica Sinica2025
Anti-EGFR therapy can overcome acquired resistance to the third-generation ALK-tyrosine kinase inhibitor lorlatinib mediated by activation of EGFR.
Article in Acta pharmacologica Sinica, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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Who cites it
2 citing papers in PubMed.
- ALK rearrangements and resistance mutations in non-small cell lung cancer: molecular mechanisms and therapeutic implications.Cancer chemotherapy and pharmacology · 2026Review
- R2HaPpY: Rapid-robust phosphotyrosine peptide enrichment using HaloTag-Src SH2 pY superbinder.bioRxiv : the preprint server for biology · 2025Article
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Authors and funding
14 authors.
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Abstract
Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related mortality. Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are standard treatments for EML4-ALK-positive NSCLC, but resistance to these agents remains a challenge. This study aimed to determine the mechanisms of acquired resistance to the third-generation ALK-TKI lorlatinib. Lorlatinib-resistant cell lines were established by prolonged exposure to a high concentration of lorlatinib. Activation of epidermal growth factor receptor (EGFR) caused by a decrease in endocytosis and degradation of protein was demonstrated to play an essential role in acquired resistance to lorlatinib. The interaction between the EGFR and ALK was investigated to identify binding sites and conformational changes in ALK. We performed high-throughput compound screening using a small-molecule drugs library comprising 510 antitumor agents in an effort to discover small-molecule compounds that target EGFR in lorlatinib-resistant cells. Combination treatment with ALK-TKI and anti-EGFR agents suppressed acquired resistance to ALK-TKIs caused by activation of EGFR in vitro and in vivo, suggesting that the combination of lorlatinib and an anti-EGFR agent could be effective in patients with lorlatinib-resistant NSCLC. This research provides insights into the mechanism of resistance to lorlatinib and suggests that it can be overcome by anti-EGFR treatment, offering a promising approach for treating resistance to lorlatinib mediated by EGFR activation in patients with ALK-positive NSCLC.
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