87 BEZ235, a dual PI3K/mTORC inhibitor, targets the DNA damage response leading to radiosensitization and senescence

Abstract

Growth factors and their receptors play an important role in the pathogenesis of human cancer. The human epidermal growth factor receptor-2 (HER2) is overexpressed in approximately 30% of breast cancers and this is associated with poor clinical outcome. Overexpression of HER2 has been demonstrated to play a direct role in oncogenic transformation. Murine monoclonal antibodies (muMAbs) targeting the extracellular domain of the HER2 receptors suppress HER2-positive cancer cell growth, with muMAb 4D5 having particularly potent activity. A humanized form of muMAb 4D5 was generated by converting all but the antigen-binding region of muMAb 4D5 into human IgG consensus sequences. The humanized monoclonal antibody, Herceptin®, preferentially targets HER2-overexpressing cells, produces responses in breast cancer patients and is well tolerated. In a pivotal phase III trial, Herceptin®administered in combination with chemotherapy (anthracycline/cyclophosphamide or paclitaxel) was compared with chemotherapy alone. The combination was found to produce significant survival benefits in HER2-positive metastatic breast cancer patients. These results have led to the approval of Herceptin®for clinical use in the USA and elsewhere.