Intrinsic caspase-8 activation mediates sensitization of erlotinib-resistant tumor cells to erlotinib/cell-cycle inhibitors combination treatment
Por:
M. ORZAEZ, T. GUEVARA, M. SANCHO and E. PEREZ-PAYA
Publicada:
1 oct 2012
Resumen:
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.
Cell Death and Disease (2012) 3, e415; doi:10.1038/cddis.2012.155; published online 25 October 2012
Filiaciones:
:
Ctr Invest Principe Felipe, Lab Peptide & Prot Chem, E-46012 Valencia, Spain
T. GUEVARA:
Ctr Invest Principe Felipe, Lab Peptide & Prot Chem, E-46012 Valencia, Spain
CSIC, IBV, Valencia, Spain
:
Ctr Invest Principe Felipe, Lab Peptide & Prot Chem, E-46012 Valencia, Spain
:
Ctr Invest Principe Felipe, Lab Peptide & Prot Chem, E-46012 Valencia, Spain
CSIC, IBV, Valencia, Spain
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