title: Intrinsic caspase-8 activation mediates sensitization of erlotinib-resistant tumor cells to erlotinib/cell-cycle inhibitors combination treatment.
abstract: Inhibitors of the tyrosine kinase activity of epidermal growth factor receptor, as erlotinib, have an established role in treating several cancer types. However, resistance to erlotinib, particularly in breast cancer cell lines, and erlotinib treatment-associated disorders have also been described. Also, methods and combination therapies that could reverse resistance and ameliorate non-desirable effects represent a clinical challenge. Here, we show that the ATP non-competitive CDK2/cyclin A inhibitor NBI1 sensitizes erlotinib-resistant tumor cells to the combination treatment (co-treatment) for apoptosis-mediated cell death. Furthermore, in erlotinib-sensitive cells, the effective dose of erlotinib was lower in the presence of NBI1. The analysis in the breast cancer MDA-MB-468 erlotinib-resistant and in lung cancer A549 cell lines of the molecular mechanism underlying the apoptosis induced by co-treatment highlighted that the accumulation of DNA defects and depletion of cIAP and XIAP activates the ripoptosome that ultimately activates caspases-8 and -10 and apoptosis. This finding could have significant implications for future treatment strategies in clinical settings.
authors.affiliation: Laboratory of Peptide and Protein Chemistry, Centro de Investigación Príncipe Felipe, Valencia, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Orzáez
authors.forename: T
authors.initials: T
authors.lastname: Guevara
authors.forename: M
authors.initials: M
authors.lastname: Sancho
authors.forename: E
authors.initials: E
authors.lastname: Pérez-Payá
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019925:Cyclin A / Q000037:antagonists & inhibitors*; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004359:Drug Therapy, Combination; D000069347:Erlotinib Hydrochloride; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D011799:Quinazolines / Q000494:pharmacology*
chemical_list: D019925:Cyclin A; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D053181:Caspase 8