title: EGF receptor inhibition radiosensitizes NSCLC cells by inducing senescence in cells sustaining DNA double-strand breaks.
abstract: 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.
authors.affiliation: Laboratory of Cellular & Molecular Radiation Oncology, Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts, USA.
authors.forename: Meng
authors.initials: M
authors.lastname: Wang
authors.forename: Fabian
authors.initials: F
authors.lastname: Morsbach
authors.forename: David
authors.initials: D
authors.lastname: Sander
authors.forename: Liliana
authors.initials: L
authors.lastname: Gheorghiu
authors.forename: Akash
authors.initials: A
authors.lastname: Nanda
authors.forename: Cyril
authors.initials: C
authors.lastname: Benes
authors.forename: Malte
authors.initials: M
authors.lastname: Kriegs
authors.forename: Mechthild
authors.initials: M
authors.lastname: Krause
authors.forename: Ekkehard
authors.initials: E
authors.lastname: Dikomey
authors.forename: Michael
authors.initials: M
authors.lastname: Baumann
authors.forename: Jochen
authors.initials: J
authors.lastname: Dahm-Daphi
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Settleman
authors.forename: Henning
authors.initials: H
authors.lastname: Willers
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects / Q000528:radiation effects*; D000068818:Cetuximab; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects / Q000528:radiation effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D011838:Radiation-Sensitizing Agents; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D011838:Radiation-Sensitizing Agents; D016159:Tumor Suppressor Protein p53; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D000068818:Cetuximab