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

  • Oncotarget. 2016 Jun 14;7(24):37013-37029. doi: 10.18632/oncotarget.9455.
Christophe Le Clorennec  1  2  3  4 ,  Yassamine Lazrek  1  2  3  4  5  6 ,  Olivier Dubreuil  5  7 ,  Christel Larbouret  1  2  3  4 ,  Marie-Alix Poul  1  2  3  4 ,  Philippe Mondon  5  8 ,  Gerry Melino  9  10 ,  André Pèlegrin  1  2  3  4 ,  Thierry Chardès  1  2  3  4
Affiliations
  • 1. IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France.
  • 2. INSERM, U1194 Montpellier, Montpellier, F-34298, France.
  • 3. Université de Montpellier, Montpellier, F-34298, France.
  • 4. ICM, Institut Régional du Cancer Montpellier, Montpellier, F-34298, France.
  • 5. Millegen SA, Labège, F-31670, France.
  • 6. Institut Pasteur de Guyane, BP 6010, 97306, Cayenne Cedex, France.
  • 7. GamaMabs Pharma SA, Centre Pierre Potier, ONCOPOLE, BP 50624, France.
  • 8. LFB Biotechnologies, 59000, Lille, France.
  • 9. Biochemistry Laboratory, Instituto Dermopatico Dell'Immacolata, Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata," 00133 Rome, Italy.
  • 10. Toxicology Unit, Medical Research Council, Leicester University, Leicester LE1 9HN, United Kingdom.
PMID: 27203743 DOI: 10.18632/oncotarget.9455
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.

Keywords
HER3; ITCH/AIP4; antibody; cancer; treatment.