Oncotarget

Research Papers:

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

Christophe Le Clorennec, Yassamine Lazrek, Olivier Dubreuil, Christel Larbouret, Marie-Alix Poul, Philippe Mondon, Gerry Melino, André Pèlegrin, Thierry Chardès _

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Oncotarget. 2016; 7:37013-37029. https://doi.org/10.18632/oncotarget.9455

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Abstract

Christophe Le Clorennec1,2,3,4, Yassamine Lazrek1,2,3,4,5,8, Olivier Dubreuil5,9, Christel Larbouret1,2,3,4, Marie-Alix Poul1,2,3,4, Philippe Mondon5,10, Gerry Melino6,7, André Pèlegrin1,2,3,4, Thierry Chardès1,2,3,4

1IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France

2INSERM, U1194 Montpellier, Montpellier, F-34298, France

3Université de Montpellier, Montpellier, F-34298, France

4ICM, Institut Régional du Cancer Montpellier, Montpellier, F-34298, France

5Millegen SA, Labège, F-31670, France

6Biochemistry Laboratory, Instituto Dermopatico Dell'Immacolata, Department of Experimental Medicine and Surgery, University of Rome “Tor Vergata,” 00133 Rome, Italy

7Toxicology Unit, Medical Research Council, Leicester University, Leicester LE1 9HN, United Kingdom

8Institut Pasteur de Guyane, BP 6010, 97306, Cayenne Cedex, France

9GamaMabs Pharma SA, Centre Pierre Potier, ONCOPOLE, BP 50624, France

10LFB Biotechnologies, 59000, Lille, France

Correspondence to:

Thierry Chardès, email: thierry.chardes@inserm.fr

Keywords: cancer, HER3, ITCH/AIP4, antibody, treatment

Received: January 06, 2016     Accepted: April 16, 2016     Published: May 18, 2016

ABSTRACT

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.


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