title: Anti-EGFR monoclonal antibodies enhance sensitivity to DNA-damaging agents in BRCA1-mutated and PTEN-wild-type triple-negative breast cancer cells.
abstract: Increased epidermal growth factor receptor (EGFR) expression in triple-negative breast cancer (TNBC) is recognized as a promising therapeutic target, specifically through the use of selective EGFR inhibitors combined with chemotherapies. TNBC is characterized by genetic instability that leads to increased sensitivity to cytotoxic agents. We analyzed the effect of anti-EGFR monoclonal antibodies (mAbs; cetuximab and panitumumab) in combination with chemotherapeutic agents (docetaxel, cisplatin, and epirubicin) on EGFR-expressing TNBC cell lines that have different mutation statuses for one oncogene (KRAS) and two tumor suppressor genes (PTEN and BRCA1). Both mAbs failed to improve the cytotoxic effect of chemotherapies in the KRAS mutant cell line (MDA-MB-231) and PTEN-null cell lines (HCC-1937 and MDA-MB-468). In contrast, mAbs combined with DNA-damaging agents (cisplatin or epirubicin) had a synergistic effect in the BRCA1-mutant cell line SUM-1315 (wild-type KRAS and PTEN). The reintroduction of wild-type BRCA1 into SUM-1315 cells abolished this synergism. The improved effect of combination therapy was associated with cell cycle arrest at G1 phase and inhibition of the phosphorylation of EGFR and ERK1/2 proteins. These results suggest that patients with BRCA1-associated TNBC without genetic alterations in the PTEN and KRAS genes may have improved therapeutic responses to anti-EGFR mAbs combined with DNA-damaging agents. © 2017 Wiley Periodicals, Inc.
authors.affiliation: Centre Jean Perrin-ERTICa-EA4677, Clermont-Ferrand Cedex, France.|Clermont Université-Université d'Auvergne-ERTICa-EA4677, Faculté de Médecine, Clermont-Ferrand, France.
authors.forename: Abderrahim
authors.initials: A
authors.lastname: El Guerrab
authors.affiliation: Clermont Université-Université d'Auvergne-ERTICa-EA4677, Faculté de Médecine, Clermont-Ferrand, France.|Clermont Université-Université d'Auvergne-ERTICa-EA4677, Institut Universitaire de Technologie, Département Génie Biologique, Ensemble universitaire des Cézeaux, Aubière cedex, France.
authors.forename: Mahchid
authors.initials: M
authors.lastname: Bamdad
authors.affiliation: Centre Jean Perrin-ERTICa-EA4677, Clermont-Ferrand Cedex, France.|Clermont Université-Université d'Auvergne-ERTICa-EA4677, Faculté de Médecine, Clermont-Ferrand, France.|Centre de Ressources Biologiques BB-0033-00075, Centre Jean Perrin, Clermont-Ferrand, France.
authors.forename: Yves-Jean
authors.initials: YJ
authors.lastname: Bignon
authors.affiliation: Centre Jean Perrin-ERTICa-EA4677, Clermont-Ferrand Cedex, France.|Clermont Université-Université d'Auvergne-ERTICa-EA4677, Faculté de Médecine, Clermont-Ferrand, France.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Penault-Llorca
authors.affiliation: Centre Jean Perrin-ERTICa-EA4677, Clermont-Ferrand Cedex, France.|Clermont Université-Université d'Auvergne-ERTICa-EA4677, Faculté de Médecine, Clermont-Ferrand, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Aubel
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D019313:BRCA1 Protein / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000068818:Cetuximab / Q000008:administration & dosage; D002945:Cisplatin / Q000008:administration & dosage; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D000077143:Docetaxel; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000276:immunology; D005260:Female; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics; D000077544:Panitumumab; D043823:Taxoids / Q000008:administration & dosage; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D043823:Taxoids; D000077143:Docetaxel; D000077544:Panitumumab; C512478:EGFR protein, human; D066246:ErbB Receptors; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D000068818:Cetuximab; D002945:Cisplatin
keywords: Anti-EGFR targeted therapy; chemotherapeutic agents; cytotoxicity; epidermal growth factor receptor