ArticleACS pharmacology & translational science2023
Circumvention of Gefitinib Resistance by Repurposing Flunarizine via Histone Deacetylase Inhibition.
Article in ACS pharmacology & translational science, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed, 8 citations in OpenAlex.
- Multi-Target Antitumor Effects of Natural Products and Approved Drug Repurposing in Non-Small Cell Lung Cancer: Advances in Mechanisms, Combination Regimens, Delivery System Optimization, and Clinical Challenges.International journal of molecular sciences · 2026Review
- Flunarizine changes microRNA expression in cell cultures and in a mouse model of spinal muscular atrophy.Scientific reports · 2026Article
- Phenotypic plasticity in a novel set of EGFR tyrosine kinase inhibitor-adapted non-small cell lung cancer cell lines.FEBS open bio · 2025Article
- Calcium channels as pharmacological targets for cancer therapy.Clinical and experimental medicine · 2025Review
- SJB2-043, a USP1 Inhibitor, Suppresses A549 Cell Proliferation, Migration, and EMT via Modulation of PI3K/AKT/mTOR, MAPK, and Wnt Signaling Pathways.Current issues in molecular biology · 2025Article
- HDAC8 Enhances the Function of HIF-2α by Deacetylating ETS1 to Decrease the Sensitivity of TKIs in ccRCC.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Gefitinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) for treating advanced non-small cell lung cancer (NSCLC). However, drug resistance seriously impedes the clinical efficacy of gefitinib. This study investigated the repositioning of the non-oncology drug capable of inhibiting histone deacetylases (HDACs) to overcome gefitinib resistance. A few drug candidates were identified using the in silico repurposing tool "DRUGSURV" and tested for HDAC inhibition. Flunarizine, originally indicated for migraine prophylaxis and vertigo treatment, was selected for detailed investigation in NSCLC cell lines harboring a range of different gefitinib resistance mechanisms (EGFR T790M, KRAS G12S, MET amplification, or PTEN loss). The circumvention of gefitinib resistance by flunarizine was further demonstrated in an EGFR TKI (erlotinib)-refractory patient-derived tumor xenograft (PDX) model in vivo. The acetylation level of cellular histone protein was increased by flunarizine in a concentration- and time-dependent manner. Among the NSCLC cell lines evaluated, the extent of gefitinib resistance circumvention by flunarizine was found to be the most pronounced in EGFR T790M-bearing H1975 cells. The gefitinib-flunarizine combination was shown to induce the apoptotic protein Bim but reduce the antiapoptotic protein Bcl-2, which apparently circumvented gefitinib resistance. The induction of Bim by flunarizine was accompanied by an increase in the histone acetylation and E2F1 interaction with the
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Registered trials
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