IL-17E synergizes with EGF and confers in vitro resistance to EGFR-targeted therapies in TNBC cells
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Yacine Merrouche1,2,*, Joseph Fabre1,2,*, Herve Cure3,4, Christian Garbar1,2, Camille Fuselier1,2, Jeremy Bastid5, Frank Antonicelli2, Reem Al-Daccak6,7,#, Armand Bensussan5,6,7,#, Jerome Giustiniani1,2,#
1Institut Jean Godinot, Unicancer, F-51726 Reims, France
2Université Reims-Champagne-Ardenne, DERM-I-C, EA7319, 51095 Reims, France
3CHU-Grenoble Alpes, CS 10217, 38043 La Tronche, France
4Institut National de la Santé et de la Recherche Médicale (INSERM) U823, Centre de Recherche (CRI), Institut Albert Bonniot, 38043 La Tronche, France
5OREGA Biotech, F-69130 Ecully, France
6Institut National de la Santé et de la Recherche Médicale (INSERM) UMR-S 976, Hôpital Saint Louis, 75010 Paris, France
7Université Paris Diderot, Sorbonne Paris Cité, Laboratoire Immunologie Dermatologie and Oncologie, UMR-S 976, F-75475, Paris, France
*Co-first authors, these authors contributed equally to this work
#These authors have contributed equally and share senior authorship
Jerome Giustiniani, email: firstname.lastname@example.org
Reem Al-Daccak, email: email@example.com
Keywords: IL-17E, breast cancer, EGFR, resistance, TNBC
Received: May 27, 2016 Accepted: July 13, 2016 Published: July 23, 2016
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.
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