title: IL-17E synergizes with EGF and confers in vitro resistance to EGFR-targeted therapies in TNBC cells.
abstract: Estrogen receptor-, progesterone receptor- and HER2-negative breast cancers, also known as triple-negative breast cancers (TNBCs), have poor prognoses and are refractory to current therapeutic agents, including epidermal growth factor receptor (EGFR) inhibitors. Resistance to anti-EGFR therapeutic agents is often associated with sustained kinase phosphorylation, which promotes EGFR activation and translocation to the nucleus and prevents these agents from acting on their targets. The mechanisms underlying this resistance have not been fully elucidated. In addition, the IL-17E receptor is overexpressed in TNBC tumors and is associated with a poor prognosis. We have previously reported that IL-17E promotes TNBC resistance to anti-mitotic therapies. Here, we investigated whether IL-17E promotes TNBC resistance to anti-EGFR therapeutic agents by exploring the link between the IL-17E/IL-17E receptor axis and EGF signaling. We found that IL-17E, similarly to EGF, activates the EGFR in TNBC cells that are resistant to EGFR inhibitors. It also activates the PYK-2, Src and STAT3 kinases, which are essential for EGFR activation and nuclear translocation. IL-17E binds its specific receptor, IL-17RA/IL17RB, on these TNBC cells and synergizes with the EGF signaling pathway, thereby inducing Src-dependent EGFR transactivation and pSTAT3 and pEGFR translocation to the nucleus. Collectively, our data indicate that the IL-17E/IL-17E receptor axis may underlie TNBC resistance to EGFR inhibitors and suggest that inhibiting IL-17E or its receptor in combination with EGFR inhibitor administration may improve TNBC management.
authors.affiliation: Institut Jean Godinot, Unicancer, F-51726 Reims, France.|Université Reims-Champagne-Ardenne, DERM-I-C, EA7319, 51095 Reims, France.
authors.forename: Yacine
authors.initials: Y
authors.lastname: Merrouche
authors.affiliation: Institut Jean Godinot, Unicancer, F-51726 Reims, France.|Université Reims-Champagne-Ardenne, DERM-I-C, EA7319, 51095 Reims, France.
authors.forename: Joseph
authors.initials: J
authors.lastname: Fabre
authors.affiliation: CHU-Grenoble Alpes, CS 10217, 38043 La Tronche, France.|Institut National de la Santé et de la Recherche Médicale (INSERM) U823, Centre de Recherche (CRI), Institut Albert Bonniot, 38043 La Tronche, France.
authors.forename: Herve
authors.initials: H
authors.lastname: Cure
authors.affiliation: Institut Jean Godinot, Unicancer, F-51726 Reims, France.|Université Reims-Champagne-Ardenne, DERM-I-C, EA7319, 51095 Reims, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Garbar
authors.affiliation: Institut Jean Godinot, Unicancer, F-51726 Reims, France.|Université Reims-Champagne-Ardenne, DERM-I-C, EA7319, 51095 Reims, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Fuselier
authors.affiliation: OREGA Biotech, F-69130 Ecully, France.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Bastid
authors.affiliation: Université Reims-Champagne-Ardenne, DERM-I-C, EA7319, 51095 Reims, France.
authors.forename: Frank
authors.initials: F
authors.lastname: Antonicelli
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) UMR-S 976, Hôpital Saint Louis, 75010 Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, Laboratoire Immunologie Dermatologie and Oncologie, UMR-S 976, F-75475, Paris, France.
authors.forename: Reem
authors.initials: R
authors.lastname: Al-Daccak
authors.affiliation: OREGA Biotech, F-69130 Ecully, France.|Institut National de la Santé et de la Recherche Médicale (INSERM) UMR-S 976, Hôpital Saint Louis, 75010 Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, Laboratoire Immunologie Dermatologie and Oncologie, UMR-S 976, F-75475, Paris, France.
authors.forename: Armand
authors.initials: A
authors.lastname: Bensussan
authors.affiliation: Institut Jean Godinot, Unicancer, F-51726 Reims, France.|Université Reims-Champagne-Ardenne, DERM-I-C, EA7319, 51095 Reims, France.
authors.forename: Jerome
authors.initials: J
authors.lastname: Giustiniani
mesh_terms: D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D006801:Humans; D020381:Interleukin-17 / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology
chemical_list: D020381:Interleukin-17; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D050796:STAT3 Transcription Factor; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D000077156:Gefitinib
keywords: EGFR; IL-17E; TNBC; breast cancer; resistance