Anti-EGFR monoclonal antibodies and EGFR tyrosine kinase inhibitors as combination therapy for triple-negative breast cancer
Open Access
- 15 September 2016
- journal article
- Published by Impact Journals, LLC in Oncotarget
- Vol. 7 (45), 73618-73637
- https://doi.org/10.18632/oncotarget.12037
Abstract
// <![CDATA[ $('.header-date').hide();$('#titleAuthors').hide();$('#abstractHeader').hide(); // ]]> Abderrahim El Guerrab1, 2, Mahchid Bamdad2, 3, Fabrice Kwiatkowski1, Yves-Jean Bignon1, 2, *, Frédérique Penault-Llorca1, 2, *, Corinne Aubel1, 2 1Centre Jean Perrin - ERTICa-EA4677, BP392, 63011 Clermont-Ferrand Cedex, France 2Clermont Université - Université d’Auvergne - ERTICa-EA4677, Faculté de Médecine, BP38, 63001 Clermont-Ferrand Cedex, France 3Clermont Université - Université d’Auvergne - ERTICa-EA4677, Institut Universitaire de Technologie, Département Génie Biologique, Ensemble Universitaire des Cézeaux, BP86, 63172 Aubière Cedex, France *These authors have contributed equally to this work Correspondence to: Yves-Jean Bignon, email: Yves-Jean.bignon@cjp.fr Keywords: triple-negative breast cancer, epidermal growth factor receptor, anti-EGFR targeted therapy, cytotoxicity, cell cycle Received: November 09, 2015 Accepted: August 22, 2016 Published: September 15, 2016 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.Keywords
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