Efficacy of Patritumab (U3-1287), a Fully Human Anti–Human Epidermal Growth Factor Receptor 3 (Her3) Monoclonal Antibody (Mab), in Head and Neck (H&N) Cancer Models

Abstract

ABSTRACT Aim: Activation of the receptor tyrosine kinase HER3 and its downstream signaling pathways promote the development of various cancers. HER3 facilitates phosphatidylinositol-3-kinase/AKT signaling via heterodimeric interaction with other HER family members, mediated by binding of the HER3 ligand heregulin (HRG). Patritumab (P) competes with HRG for receptor binding and mediates internalization of HER3. We examined expression of HRG in H&N cancer models and patient samples and evaluated the in vitro and in vivo efficacy of P alone or with cetuximab (C). Methods: Selection of H&N cell lines for reverse transcription polymerase chain reaction was based on microarray data. Tumor cells were treated with 10 µg/mL of P, C, or a combination of both, and cell lysates were analyzed for HER3/pHER3-, AKT/pAKT- and extracellular regulated kinase (ERK)/pERK-levels by Western blotting. The effect of P and C on proliferation and apoptosis was evaluated by bromodeoxyuridine- and caspase-3/7 assays. To address efficacy in vivo, mice bearing tumor xenografts were treated with P and/or C twice weekly, and tumor volumes were assessed. HRG expression was also evaluated in patient samples. Results: HRG expression was frequent in H&N cell lines. HRG mRNA expression was elevated in 67% of patient tumor samples compared with controls. In H&N cell lines, basal HER3 and AKT activation were inhibited by P, with additional blockage of the ERK pathway by co-treatment with C. In vitro combination effects were also observed on the inhibition of proliferation and caspase-3/7 activation. Co-administration of P + C enhanced tumor growth inhibition (TGI) in vivo. Conclusions: High expression frequencies of HRG were observed in H&N tumor cell lines and patient samples, and were associated with single-agent efficacy of P on cell signaling in vitro and on TGI in vivo. The combination of P + C extended the inhibition of signaling pathways, induced apoptosis and inhibited proliferation in vitro, and enforced TGI in vivo. Thus, these data strongly support the combination of P with an anti-epidermal growth factor receptor mAb as a promising strategy for the treatment of H&N cancer. Disclosure: All authors have declared no conflicts of interest.