Insulin‐like growth factor‐1 receptor as a novel prognostic marker and its implication as a cotarget in the treatment of human adenocarcinoma of the esophagus

Insulin‐like growth factor‐1 receptor (IGF‐1R) and human epidermal growth factor receptor‐2 (HER2) receptor expression has been found to be a key regulator of tumorigenesis. The purpose of our study was to establish the prognostic significance of IGF‐1R in esophageal cancer and to determine the effect of IGF‐1R and HER2 targeting with α‐IR3 and Herceptin™ antibodies on the proliferation of esophageal cancer cells in vitro. IGF‐1R expression and clinicopathological correlations were analyzed with a tissue microarray containing 234 esophageal cancer specimens (133 adenocarcinomas and 101 squamous cell carcinomas). Proliferation changes associated with Herceptin™ and α‐IR3 blockage were evaluated with the unique human esophageal cancer cell lines Pt1590 and LN1590. IGF‐1R and HER2 expression levels, activation and phosphorylation status of downstream signaling proteins involved in the activation pathways were analyzed by Western blotting. IGF‐1R overexpression was detected in 121 (52%) of the 234 esophageal tumors examined. In the subgroup of 87 HER2‐positive tumors, 93.1% showed concordant overexpression for IGF‐1R. IGF‐1R was identified as a variable associated with reduced overall survival for adenocarcinoma (p = 0.05), but not for squamous cell carcinoma. The combination of Herceptin™ and α‐IR3 was more effective in inhibiting in vitro proliferation than treatment with either agent alone (p < 0.01). This was associated with a decrease in HER2 and IGF‐1R protein levels and suppression of Akt‐ and MAP kinase phosphorylation. IGF‐1R expression can be used as a novel prognostic marker for adenocarcinomas of the esophagus. Cotreatment with IGF‐1R and HER2 antibodies might become a valuable and effective treatment option in esophageal adenocarcinoma.