Activation of ERBB2 Signaling Causes Resistance to the EGFR-Directed Therapeutic Antibody Cetuximab

摘要: Cetuximab, an antibody directed against the epidermal growth factor receptor, is effective clinical therapy for patients with colorectal, head and neck, non–small cell lung cancer, particularly those KRAS BRAF wild-type cancers. Treatment in all limited eventually by development of acquired resistance, but little known about underlying mechanism. Here, we show that activation ERBB2 signaling lines, either through amplification or heregulin up-regulation, leads to persistent extracellular signal–regulated kinase 1/2 consequently cetuximab resistance. Inhibition disruption ERBB2/ERBB3 heterodimerization restores sensitivity vitro vivo. A subset colorectal cancer who exhibit de novo resistance cetuximab-based has high levels circulating heregulin. Collectively, these findings identify two distinct mechanisms, both which promote aberrant signaling, mediate Moreover, results suggest inhibitors, combination cetuximab, represent a rational therapeutic strategy should be assessed cetuximab-resistant