EGF-R Small Inhibitors and Anti-EGF-R Antibodies: Advantages and Limits of a New Avenue in Anticancer Therapy

Michele      Caraglia; Monica      Marra; Giusy      Meo; Raffaele      Addeo; Pierosandro      Tagliaferri; Alfredo      Budillon

Abstract

Cellular receptors for the Epidermal Growth Factor (EGF-R) are members of the ErbB receptor family and are considered important targets for the experimental treatment of human cancer. Monoclonal antibodies as well as small tyrosine kinase inhibitors (TKIs) have been developed and have undergone extensive evaluation in preclinical and clinical studies based on the general idea that EGF-R plays a critical role on the growth and survival of human tumors. This assumption has been derived by the successful development of BCR/ABL tyrosine kinase inhibitors in human chronic myeloid leukemia as well as on the activity of therapy with monoclonal antibodies (mAb) in breast cancer and lymphoproliferative diseases. It is now becoming clear that factors regulating sensitivity to kinase inhibitors may differ from monoclonal antibodies and that the molecules targeted by interfering drugs must be prioritaire for growth and survival of those specific tumors in order to achieve valuable results. In this article, we will describe the signal transduction pathways regulated by EGF-R and the principal pharmacological and biotechnological agents directed against EGF-R. We will discuss the significance of targeting the EGF-R driven survival pathways and the compensatory intracellular survival mechanisms that counteract the specific EGF-R inhibition and are the cause of the poor clinical results derived from study based on the use of these agents. We will describe new multipotent TKIs that target also other members of ErbB family (i.e. ErbB2) blocking one of the compensatory mechanism that can be triggered in cancer cells. Moreover, we will report new patent on bispecific mAbs that bind EGF-R and immune effectors in order to increase the immunological function of this agent that could be the basis of the different clinical results achieved with the use of TKI and mAbs. Finally, we will propose a pharmacological model able to make cancer cells dependent on EGF-R for their survival and proliferation and we will discuss the relevance of patenting also new therapeutical strategies and not only the simple drug.

Keywords: Epidermal growth factor receptor (EGF-R), ErbB family receptors, ErbB2, anti-EGF-R tyrosine kinase inhibitors, dual tyrosine kinase inhibitors, Raf-1, Erk, Akt, anti-EGF-R antibodies, bispecific anti-EGF-R and anti-CD3 antibodies