title: TC-N19, a novel dual inhibitor of EGFR and cMET, efficiently overcomes EGFR-TKI resistance in non-small-cell lung cancer cells.
abstract: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) show a clinical benefit when used to treat patients with EGFR-mutated non-small-cell lung cancer (NSCLC), but this treatment unfortunately fails in patients with TKI-resistant tumors. We here provide evidence that TC-N19 (N19), a novel dual inhibitor of EGFR and cMET, efficiently overcomes the EGFR-TKI resistance in EGFR-mutated NSCLC cells via simultaneous degradation of both proteins by ubiquitin proteasomes. Comparison with HSP90 inhibitor treatment and knockdown of EGFR and cMET by small hairpin RNAs reveal that the reduction of EGFR and cMET expression by N19 is responsible for overcoming the intrinsic TKI resistance mediated by paxillin (PXN) in high PXN-expressing cells, PXN-overexpressing PC9 cells (PC9-PXN), the EGFR-T790M-mediated TKI resistance in H1975 and CL97 cells, and the acquired resistance to gefitinib in gefitinib-resistant PC9 cells (PC9GR). Annexin V-PI staining assay showed that the induction of apoptosis in NSCLC cells by N19 depended on the reduction in levels of both proteins. Xenograft tumor formation in nude mice induced by a PC9-PXN-stable clone and by PC9GR cells was nearly completely suppressed by N19 treatment, with no changes in animal body weight. MTT assays of normal lung cells and reticulocytes showed no cytotoxicity responses to N19. In summary, N19 may act as a novel dual inhibitor of EGFR and cMET that induces apoptosis in TKI-resistant EGFR-mutated NSCLC cells and suppresses xenograft tumor formation. We suggest that N19 may be a potential new-generation TKI or HSP90 inhibitor used for treatment of NSCLC patients who show resistance to current TKI-targeting therapies.
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: D-W
authors.initials: DW
authors.lastname: Wu
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: T-C
authors.initials: TC
authors.lastname: Chen
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: H-S
authors.initials: HS
authors.lastname: Huang
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: H
authors.initials: H
authors.lastname: Lee
mesh_terms: D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077156:Gefitinib; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D059748:Proteolysis / Q000187:drug effects; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D014410:Tumor Stem Cell Assay; D025801:Ubiquitin / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D000880:Anthraquinones; D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D025801:Ubiquitin; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D046988:Proteasome Endopeptidase Complex; D000077156:Gefitinib