title: Dual targeting of ErbB-2/ErbB-3 results in enhanced antitumor activity in preclinical models of pancreatic cancer.
abstract: ErbB-3 and its ligand NRG-1β are key players in driving oncogenic signaling and resistance to therapy through the activation of the PI3K/Akt pathway. We have recently reported that EV20, a humanized anti-ErbB3 antibody, possesses a marked antitumor activity in a variety of human tumor models, including pancreatic cancer (PC). Here, we report that despite epidermal growth factor receptor overexpression, PC cells are more sensitive to NRG-1β than EGF in terms of Akt activation and cell proliferation. Using stable ErbB-3-knocked down cells and EV20 in combination with trastuzumab, we showed that dual targeting of ErbB-2 and ErbB-3 was necessary to completely abrogate ErbB-3 signaling and to impair cell proliferation. Similarly, enhanced therapeutic efficacy of the antibody combination was seen in xenografts originating from K-Ras-mutated HPAF-II and SW1990 cells, without increasing the toxicity. These results indicate that dual targeting of ErbB-2 and ErbB-3 could represent a new therapeutic approach in PC.Oncogenesis (2014) 3, e117; doi:10.1038/oncsis.2014.31; published online 18 August 2014.
authors.affiliation: 1] Department of Experimental and Clinical Sciences, G. D'Annunzio University and Foundation, Chieti, Italy [2] Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran.
authors.forename: R
authors.initials: R
authors.lastname: Ghasemi
authors.affiliation: Department of Experimental and Clinical Sciences, G. D'Annunzio University and Foundation, Chieti, Italy.
authors.forename: I G
authors.initials: IG
authors.lastname: Rapposelli
authors.affiliation: Department of Experimental and Clinical Sciences, G. D'Annunzio University and Foundation, Chieti, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Capone
authors.affiliation: Center of Excellence on Aging (CeSI), Chieti, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Rossi
authors.affiliation: Department of Experimental and Clinical Sciences, G. D'Annunzio University and Foundation, Chieti, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Lattanzio
authors.affiliation: 1] Department of Experimental and Clinical Sciences, G. D'Annunzio University and Foundation, Chieti, Italy [2] MediaPharma s.r.l., Via dei Vestini 31, Chieti, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Piantelli
authors.affiliation: 1] Department of Experimental and Clinical Sciences, G. D'Annunzio University and Foundation, Chieti, Italy [2] MediaPharma s.r.l., Via dei Vestini 31, Chieti, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Sala
authors.affiliation: MediaPharma s.r.l., Via dei Vestini 31, Chieti, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Iacobelli