EGFR ligands and their signaling scissors, ADAMs, as new molecular targets for anticancer treatments

Abstract Members of the human epidermal growth factor receptor (HER) family of receptor tyrosine kinases and their ligands (EGFR ligands) are known to play crucial roles in the regulation of cell proliferation and differentiation, and in the survival of many types of cancer. HER family members are activated in cancer cells and are now considered to be useful molecular targets for cancer therapy. Recently, several new drugs, including monoclonal antibodies and small-molecule inhibitors that target HER members, have been developed and clinically used to treat solid tumors. Members of a disintegrin and metalloproteinase (ADAM) family are thought to mediate the shedding of EGFR ligands and this event is critical for the production of soluble functional EGFR ligands. In melanoma cells, UV irradiation activates some ADAM members and induces melanoma cell growth through EGFR ligand shedding by activated ADAMs. These findings suggest that ADAM inhibitors are also candidate anticancer drugs acting via the blockade of HER family signaling pathways. After shedding of EGFR ligands by ADAMs, the carboxy-terminal fragments (CTFs) of EGFR ligands in the cytoplasm are translocated to the nucleus and induce cell proliferation by binding and exporting repressors and activating cyclin A and c-Myc. Based on these findings, the present molecular targeting therapy against HER members, EGFR and HER2, may not be sufficient, while ADAMs and nuclear translocation of the CTF of EGFR ligands are potential targets for the treatment of cancer, particularly malignancies that are dependent on the EGF family.