Intrinsic caspase-8 activation mediates sensitization of erlotinib-resistant tumor cells to erlotinib/cell-cycle inhibitors combination treatmentCitation formats

  • Authors:
  • M Orzáez
  • T Guevara
  • M Sancho
  • E Pérez-Payá

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Intrinsic caspase-8 activation mediates sensitization of erlotinib-resistant tumor cells to erlotinib/cell-cycle inhibitors combination treatment. / Orzáez, M; Guevara, T; Sancho, M; Pérez-Payá, E.

In: CELL DEATH & DISEASE, Vol. 3, 25.10.2012, p. e415.

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@article{a17dc89a728e462fbe982b2d1f9df96c,
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.",
keywords = "Antineoplastic Combined Chemotherapy Protocols/pharmacology, Apoptosis/drug effects, Caspase 8/genetics, Cell Cycle/drug effects, Cell Line, Tumor, Cell Survival/drug effects, Cyclin A/antagonists & inhibitors, Cyclin-Dependent Kinase 2/antagonists & inhibitors, Drug Resistance, Neoplasm/drug effects, Drug Therapy, Combination, Erlotinib Hydrochloride, Humans, Neoplasms/drug therapy, Quinazolines/pharmacology",
author = "M Orz{\'a}ez and T Guevara and M Sancho and E P{\'e}rez-Pay{\'a}",
year = "2012",
month = oct,
day = "25",
doi = "10.1038/cddis.2012.155",
language = "English",
volume = "3",
pages = "e415",
journal = "Cell Death and Disease",
issn = "2041-4889",
publisher = "Springer Nature",

}

RIS

TY - JOUR

T1 - Intrinsic caspase-8 activation mediates sensitization of erlotinib-resistant tumor cells to erlotinib/cell-cycle inhibitors combination treatment

AU - Orzáez, M

AU - Guevara, T

AU - Sancho, M

AU - Pérez-Payá, E

PY - 2012/10/25

Y1 - 2012/10/25

N2 - 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.

AB - 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.

KW - Antineoplastic Combined Chemotherapy Protocols/pharmacology

KW - Apoptosis/drug effects

KW - Caspase 8/genetics

KW - Cell Cycle/drug effects

KW - Cell Line, Tumor

KW - Cell Survival/drug effects

KW - Cyclin A/antagonists & inhibitors

KW - Cyclin-Dependent Kinase 2/antagonists & inhibitors

KW - Drug Resistance, Neoplasm/drug effects

KW - Drug Therapy, Combination

KW - Erlotinib Hydrochloride

KW - Humans

KW - Neoplasms/drug therapy

KW - Quinazolines/pharmacology

U2 - 10.1038/cddis.2012.155

DO - 10.1038/cddis.2012.155

M3 - Article

C2 - 23096116

VL - 3

SP - e415

JO - Cell Death and Disease

JF - Cell Death and Disease

SN - 2041-4889

ER -