EGF receptor inhibition radiosensitizes NSCLC cells by inducing senescence in cells sustaining DNA double-strand breaks.
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EGF receptor inhibition radiosensitizes NSCLC cells by inducing senescence in cells sustaining DNA double-strand breaks. / Wang, Meng; Morsbach, Fabian; Sander, David; Gheorghiu, Liliana; Nanda, Akash; Benes, Cyril; Kriegs, Malte; Krause, Mechthild; Dikomey, Ekkehard; Baumann, Michael; Dahm-Daphi, Jochen; Settleman, Jeffrey; Willers, Henning.
In: CANCER RES, Vol. 71, No. 19, 19, 2011, p. 6261-6269.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - EGF receptor inhibition radiosensitizes NSCLC cells by inducing senescence in cells sustaining DNA double-strand breaks.
AU - Wang, Meng
AU - Morsbach, Fabian
AU - Sander, David
AU - Gheorghiu, Liliana
AU - Nanda, Akash
AU - Benes, Cyril
AU - Kriegs, Malte
AU - Krause, Mechthild
AU - Dikomey, Ekkehard
AU - Baumann, Michael
AU - Dahm-Daphi, Jochen
AU - Settleman, Jeffrey
AU - Willers, Henning
PY - 2011
Y1 - 2011
N2 - The mechanisms by which inhibition of the epidermal growth factor receptor (EGFR) sensitizes non-small cell lung cancer (NSCLC) cells to ionizing radiation remain poorly understood. We set out to characterize the radiosensitizing effects of the tyrosine kinase inhibitor erlotinib and the monoclonal antibody cetuximab in NSCLC cells that contain wild-type p53. Unexpectedly, EGFR inhibition led to pronounced cellular senescence but not apoptosis of irradiated cells, both in vitro and in vivo. Senescence was completely dependent on wild-type p53 and associated with a reduction in cell number as well as impaired clonogenic radiation survival. Study of ten additional NSCLC cell lines revealed that senescence is a prominent mechanism of radiosensitization in 45% of cell lines and occurs not only in cells with wild-type p53 but also in cells with mutant p53, where it is associated with an induction of p16. Interestingly, senescence and radiosensitization were linked to an increase in residual radiation-induced DNA double-strand breaks irrespective of p53/p16 status. This effect of EGFR inhibition was at least partially mediated by disruption of the MEK-ERK pathway. Thus, our data indicate a common mechanism of radiosensitization by erlotinib or cetuximab across diverse genetic backgrounds. Our findings also suggest that assays that are able to capture the initial proliferative delay that is associated with senescence should be useful for screening large cell line panels to identify genomic biomarkers of EGFR inhibitor-mediated radiosensitization.
AB - The mechanisms by which inhibition of the epidermal growth factor receptor (EGFR) sensitizes non-small cell lung cancer (NSCLC) cells to ionizing radiation remain poorly understood. We set out to characterize the radiosensitizing effects of the tyrosine kinase inhibitor erlotinib and the monoclonal antibody cetuximab in NSCLC cells that contain wild-type p53. Unexpectedly, EGFR inhibition led to pronounced cellular senescence but not apoptosis of irradiated cells, both in vitro and in vivo. Senescence was completely dependent on wild-type p53 and associated with a reduction in cell number as well as impaired clonogenic radiation survival. Study of ten additional NSCLC cell lines revealed that senescence is a prominent mechanism of radiosensitization in 45% of cell lines and occurs not only in cells with wild-type p53 but also in cells with mutant p53, where it is associated with an induction of p16. Interestingly, senescence and radiosensitization were linked to an increase in residual radiation-induced DNA double-strand breaks irrespective of p53/p16 status. This effect of EGFR inhibition was at least partially mediated by disruption of the MEK-ERK pathway. Thus, our data indicate a common mechanism of radiosensitization by erlotinib or cetuximab across diverse genetic backgrounds. Our findings also suggest that assays that are able to capture the initial proliferative delay that is associated with senescence should be useful for screening large cell line panels to identify genomic biomarkers of EGFR inhibitor-mediated radiosensitization.
KW - Humans
KW - Cell Line, Tumor
KW - Tumor Suppressor Protein p53/metabolism
KW - Protein Kinase Inhibitors/pharmacology
KW - Antineoplastic Agents/pharmacology
KW - Antibodies, Monoclonal/pharmacology
KW - Apoptosis/drug effects/radiation effects
KW - Carcinoma, Non-Small-Cell Lung/drug therapy/metabolism/pathology/radiotherapy
KW - Cell Aging/drug effects/radiation effects
KW - DNA Breaks, Double-Stranded/drug effects/radiation effects
KW - Lung Neoplasms/metabolism/pathology/radiotherapy
KW - Quinazolines/pharmacology
KW - Radiation-Sensitizing Agents
KW - Receptor, Epidermal Growth Factor/antagonists & inhibitors/metabolism
KW - Humans
KW - Cell Line, Tumor
KW - Tumor Suppressor Protein p53/metabolism
KW - Protein Kinase Inhibitors/pharmacology
KW - Antineoplastic Agents/pharmacology
KW - Antibodies, Monoclonal/pharmacology
KW - Apoptosis/drug effects/radiation effects
KW - Carcinoma, Non-Small-Cell Lung/drug therapy/metabolism/pathology/radiotherapy
KW - Cell Aging/drug effects/radiation effects
KW - DNA Breaks, Double-Stranded/drug effects/radiation effects
KW - Lung Neoplasms/metabolism/pathology/radiotherapy
KW - Quinazolines/pharmacology
KW - Radiation-Sensitizing Agents
KW - Receptor, Epidermal Growth Factor/antagonists & inhibitors/metabolism
M3 - SCORING: Journal article
VL - 71
SP - 6261
EP - 6269
JO - CANCER RES
JF - CANCER RES
SN - 0008-5472
IS - 19
M1 - 19
ER -
