HER-targeted tyrosine-kinase inhibitors

Improved understanding of tumor biology has led to the identification of numerous growth factors that are involved in malignant transformation and tumor progression. Many of these factors induce cellular responses through receptors with intrinsic tyrosine kinase (TK) activity. Therefore, inhibiting receptor TK activity is a way to effectively block the tumorigenic effects that arise from these pathways. The HER family of TK receptors is overexpressed or dysregulated in many types of human cancer. As a result these receptors were identified as targets for cancer therapy. Several agents have been developed that reversibly, or irreversibly, inhibit one, two or all of the HER receptors. Tarceva and Iressa are HER1-TK inhibitors that are advanced in development. Clinical data show that these agents as monotherapy have antitumor activity in patients with various types of solid tumor and are well tolerated; encouraging data are also produced when Tarceva or Iressa are combined with chemotherapeutic agents. Other dual or pan-HER, reversible or irreversible, TK inhibitors are being investigated in phase I trials. Early data show that they are generally well tolerated and have provided evidence of antitumor activity. HER-TK inhibitors are exciting agents that are likely to have a substantial impact on the way we treat patients with cancer.