The anti-HER3 (ErbB3) therapeutic antibody 9F7-F11 induces HER3 ubiquitination and degradation in tumors through JNK1/2- dependent ITCH/AIP4 activation

• Published in: Oncotarget Vol. 7; no. 24; pp. 37013 - 37029
• Main Authors: Le Clorennec, Christophe, Lazrek, Yassamine, Dubreuil, Olivier, Larbouret, Christel, Poul, Marie-Alix, Mondon, Philippe, Melino, Gerry, Pèlegrin, André, Chardès, Thierry
• Format: Journal Article
• Language: English
• Published: United States Impact journals 14-06-2016; Impact Journals LLC
• Subjects: Antibodies, Monoclonal; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal, Murine-Derived - pharmacology; Antineoplastic Agents; Antineoplastic Agents - pharmacology; Cancer; Cell Line, Tumor; Down-Regulation; Human health and pathology; Humans; Life Sciences; MAP Kinase Signaling System; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - physiology; Mitogen-Activated Protein Kinase 8; Mitogen-Activated Protein Kinase 8 - metabolism; Mitogen-Activated Protein Kinase 9; Mitogen-Activated Protein Kinase 9 - metabolism; Receptor, ErbB-3; Receptor, ErbB-3 - antagonists & inhibitors; Repressor Proteins; Repressor Proteins - drug effects; Repressor Proteins - metabolism; Research Paper; Ubiquitin-Protein Ligases; Ubiquitin-Protein Ligases - drug effects; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; treatment; ITCH/AIP4; cancer; antibody; HER3
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.9455

We characterized the mechanism of action of the neuregulin-non-competitive anti-HER3 therapeutic antibody 9F7-F11 that blocks the PI3K/AKT pathway, leading to cell cycle arrest and apoptosis in vitro and regression of pancreatic and breast cancer in vivo. We found that 9F7-F11 induces rapid HER3 down-regulation. Specifically, 9F7-F11-induced HER3 ubiquitination and degradation in pancreatic, breast and prostate cancer cell lines was driven mainly by the itchy E3 ubiquitin ligase (ITCH/AIP4). Overexpression of the ITCH/AIP4 inhibitor N4BP1 or small-interfering RNA-mediated knockdown of ITCH/AIP4 inhibited HER3 ubiquitination/degradation and PI3K/AKT signaling blockade induced by 9F7-F11. Moreover, 9F7-F11-mediated JNK1/2 phosphorylation led to ITCH/AIP4 activation and recruitment to HER3 for receptor ubiquitination and degradation. ITCH/AIP4 activity was activated by the deubiquitinases USP8 and USP9X, as demonstrated by RNA interference. Taken together, our results suggest that 9F7-F11-induced HER3 ubiquitination and degradation in cancer cells mainly occurs through JNK1/2-dependent ITCH/AIP4 activation.