Georgia Zhuo Chen
Emory University-School of Medicine, USA
Title: Optimization of EGFR-based targeted therapy and beyond
Biography
Biography: Georgia Zhuo Chen
Abstract
Cetuximab is a chimerized antibody against epidermal growth factor receptor (EGFR) and the only approved targeted agent for squamous cell carcinoma of the head and neck (SCCHN) in the US except newly developed immunotherapies. However, intrinsic and acquired resistance to EGFR targeted therapy inevitably occurs. Compensatory signaling from c-Met, HER3 and other (ErbB or HER) family members has been linked to the decreased sensitivity to EGFR-based therapy in SCCHN. We found that the expression of the HER3 activation ligand HRG1 is elevated in SCCHN compared to other solid tumors and HRG1 is an independent prognostic factor in SCCHN regardless of HPV status, suggesting a significant role of HER3 activation through HRG1 or its heterodimer partners (EGFR, HER2, and c-Met) in resistance to EGFR therapy. Simultaneously targeting c-Met and HER family members for treatments of the tumors resistant to EGFR-based therapy has shown better efficacies than any of the single targeting in animal models. In addition, accumulated evidence suggests that antibody dependent cellular cytotoxicity (ADCC) of cetuximab might result in upregulation of INFγ, while INFγ induces the expression of programmed death ligand-1 (PD-L1), an immune checkpoint receptor ligand, contributing to cetuximab resistance through an immune escape mechanism. We have recently demonstrated that the combination of cetuximab with a HER3 antibody down regulates PD-L1 more effectively than each antibody alone. It is expected therefore that elimination of intrinsic upregulation of PD-L1 using this combination may alter the T-cell profile in vivo.