title: Anti-EGFR monoclonal antibodies and EGFR tyrosine kinase inhibitors as combination therapy for triple-negative breast cancer.
abstract: Triple-negative breast cancer (TNBC) is characterized by overexpression of epidermal growth factor receptor (EGFR) and activation of its downstream signaling pathways. Dual targeting of EGFR using one monoclonal antibody (mAb; cetuximab or panitumumab) and one tyrosine kinase inhibitor (EGFR-TKI; gefitinib or erlotinib) is a potential therapeutic approach. We investigated the effect of these therapies in EGFR-expressing TNBC cell lines that do or do not harbor the main activating mutations of EGFR pathways. Cell lines were sensitive to EGFR-TKIs, whereas mAbs were active only in MDA-MB-468 (EGFR amplification) and SUM-1315 (KRAS and PTEN wild-type) cells. MDA-MB-231 (KRAS mutated) and HCC-1937 (PTEN deletion) cells were resistant to mAbs. The combined treatment resulted in a synergistic effect on cell proliferation and superior inhibition of the RAS/MAPK signaling pathway in mAb-sensitive cells. The anti-proliferative effect was associated with G1 cell cycle arrest followed by apoptosis. Sensitivity to therapies was characterized by induction of positive regulators and inactivation of negative regulators of cell cycle. These results suggest that dual EGFR inhibition might result in an enhanced antitumor effect in a subgroup of TNBC. The status of EGFR, KRAS and PTEN could be used as a molecular marker for predicting the response to this therapeutic strategy.
authors.affiliation: Centre Jean Perrin - ERTICa-EA4677, BP392, 63011 Clermont-Ferrand Cedex, France.|Clermont Université - Université d'Auvergne - ERTICa-EA4677, Faculté de Médecine, BP38, 63001 Clermont-Ferrand Cedex, France.
authors.forename: Abderrahim
authors.initials: A
authors.lastname: El Guerrab
authors.affiliation: Clermont Université - Université d'Auvergne - ERTICa-EA4677, Faculté de Médecine, BP38, 63001 Clermont-Ferrand Cedex, France.|Clermont Université - Université d'Auvergne - ERTICa-EA4677, Institut Universitaire de Technologie, Département Génie Biologique, Ensemble Universitaire des Cézeaux, BP86, 63172 Aubière Cedex, France.
authors.forename: Mahchid
authors.initials: M
authors.lastname: Bamdad
authors.affiliation: Centre Jean Perrin - ERTICa-EA4677, BP392, 63011 Clermont-Ferrand Cedex, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Kwiatkowski
authors.affiliation: Centre Jean Perrin - ERTICa-EA4677, BP392, 63011 Clermont-Ferrand Cedex, France.|Clermont Université - Université d'Auvergne - ERTICa-EA4677, Faculté de Médecine, BP38, 63001 Clermont-Ferrand Cedex, France.
authors.forename: Yves-Jean
authors.initials: YJ
authors.lastname: Bignon
authors.affiliation: Centre Jean Perrin - ERTICa-EA4677, BP392, 63011 Clermont-Ferrand Cedex, France.|Clermont Université - Université d'Auvergne - ERTICa-EA4677, Faculté de Médecine, BP38, 63001 Clermont-Ferrand Cedex, France.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Penault-Llorca
authors.affiliation: Centre Jean Perrin - ERTICa-EA4677, BP392, 63011 Clermont-Ferrand Cedex, France.|Clermont Université - Université d'Auvergne - ERTICa-EA4677, Faculté de Médecine, BP38, 63001 Clermont-Ferrand Cedex, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Aubel
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016213:Cyclins / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D058990:Molecular Targeted Therapy; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018631:ras Proteins / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D016213:Cyclins; D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins
keywords: anti-EGFR targeted therapy; cell cycle; cytotoxicity; epidermal growth factor receptor; triple-negative breast cancer