Combination of Anti-HER3 Antibody MM-121/SAR256212 and Cetuximab Inhibits Tumor Growth in Preclinical Models of Head and Neck Squamous Cell Carcinoma

Abstract

The EGFR monoclonal antibody cetuximab is the only approved targeted agent for treating head and neck squamous cell carcinoma (HNSCC). Yet resistance to cetuximab has hindered its activity in this disease. Intrinsic or compensatory HER3 signaling may contribute to cetuximab resistance. To investigate the therapeutic benefit of combining MM-121/SAR256212, an anti-HER3 monoclonal antibody, with cetuximab in HNSCC, we initially screened twelve HNSCC cell lines for total and phosphorylated levels of the four HER receptors. We also investigated the combination of MM-121 with cetuximab in preclinical models of HNSCC. Our results revealed that HER3 is widely expressed and activated in HNSCC cell lines. MM-121 strongly inhibited phosphorylation of HER3 and AKT. When combined with cetuximab, MM-121 exerted a more potent anti-tumor activity through simultaneously inhibiting the activation of HER3 and EGFR and consequently the downstream PI3K/AKT and ERK pathways in vitro. Both high and low doses of MM-121 in combination with cetuximab significantly suppressed tumor growth in xenograft models and inhibited activations of HER3, EGFR, AKT and ERK in vivo. Our current work is the first report on this new combination in HNSCC and supports the concept that HER3 inhibition may play an important role in future therapy of HNSCC. Our results open the door for further mechanistic studies to better understand the role of HER3 in resistance to EGFR inhibitors in HNSCC.

Pan-HER, an Antibody Mixture Simultaneously Targeting EGFR, HER2, and HER3, Effectively Overcomes Tumor Heterogeneity and Plasticity

“…Clearly, in the Calu-3 model system, Pan-HER eradicated tumor cells as well as inhibited proliferation of the remaining cells both in vitro and in vivo. These results are consistent with previous observations indicating that combined targeting of two HER family receptors enhances cell death and cell-cycle arrest (39,48). Although IHC analysis of the apoptosis marker cleaved caspase-3 did not show enhanced apoptosis in Pan-HER-treated BxPC3 or Calu-3 tumors (data not shown), the possibility that apoptotic cell death may have contributed to the effect earlier during the treatment period cannot be excluded.…”

CCR 20th Anniversary Commentary: A Chimeric Antibody, C225, Inhibits EGFR Activation and Tumor Growth

“…In experiments with SCCHN cell lines, treatment with the combination of cetuximab and the MM-121 mAb against HER3 produced enhancement of cell kill in culture and in xenografts (13). The mechanism involved enhanced suppression of the PI3K/AKT and ERK pathways by the mAbs against HER3 and the EGFR, respectively.…”

Emerging anti-cancer antibodies and combination therapies targeting HER3/ERBB3

“…116 Finally, the combination of MM-121 and cetuximab has been reported to inhibit head and neck tumors, in animals. 117 As reported in Table 2, several clinical trials currently examine safety and efficacy of these and additional combinations of anti-HER3 antibodies. Based on results reported in conferences, the safety of MM-121 combined with several chemotherapies (platinium or taxol) 118 or cetuximab and irinotecan 119 have been confirmed.…”