Affiliation

• ¹The Institute of Oncology, Tehran University of Medical Sciences, Tehran
• ²Sacoor Medical Group, London, United Kingdom
• ³International Centre for genetic Engineering and biotechnology, Aruna Asaf Ali Marg, New Delhi, India
• ⁴Institute of liver and biliary sciences, sector D1 vasant kunj, New Delhi, India

Corresponding Author

Prof. George Zhu, The Institute of Oncology, Tehran University of Medical Sciences, Tehran; E-mail: sansan4240732@163.com

Citation

Zhu, G., et al. Targeting Oncogenic Receptor, Currently the Standard of Care. (2017) Clin Trials Pathol Case Stud 2(2): 75- 90.

Copy rights

© 2017 Zhu, G. This is an Open access article distributed under the terms of Creative Commons Attribution 4.0 International License.

Keywords

Abstract

  In 1989 - 91, George Zhu^[1] first postulate oncogenic receptor (Voice of America, 1992, 12:31; Curr Pharm Biotechnol, 2013, 14:859 - 863), as a result of his experiments in which steroid PML-RARa fusion receptor gene rearrangement within t (15;17) translocation in acute promyelocytic leukemia (APL), and androgen cognating its (AR/ERa signaling or FGFR-1) receptor induced tumours of the breast glands in two aplastic anemia during the course of testosterone treatment (hormonal tumorigenesis). In the past 2 - 3 decades, there are at least 30 receptor genes involving in several of oncogenic process. These normal physiologic receptors linked to gene amplification, rearrangement, deletion and activating mutations, which converted receptor to oncogenic (also oncogenic receptor) in development, progressive and pathogenesis of benign and malignant diseases. Receptors included nuclear receptor family members (oncogenic estrogen/estrogen receptor alpha signaling, oncogenic androgen receptor, oncogenic pml/RARa, and GRβ); Oncogenic growth factor receptors (EGF/ oncogenic receptor EGFR, Neu oncogenic receptor, insulin receptor substrate 4 IRS4/insulin receptor/c-ros proto-oncogenic receptor, insulin and IGF-1 and -II/oncogenic IGF-1R, oncogenic PDGFAR, oncogenic TEL/PDGFRB, thrombopoietin (TPO)/TPO receptor, oncogenic MPL receptor, HGF/HGFR, met oncogenic receptor), Cytokine receptor rc family members (IL-2-BCM fusion, IL-3/oncogenic IL-3Ra, IL-7/oncogenic IL-7R and IL-21R-BCL6 fusion); Cytokine receptors including the βc family (G-CSF/oncogenic CSF3R, oncogenic EPOR), and oncogenic autocrine growth hormone/nuclear GHR and other VEGFR2. Upon ligand binding or external antigen stimuli, mutated growth factor receptors and mutant cytokine receptors including type I cytokine receptor may be activated via ligand binding receptor complex, receptor dimerizes especially receptor homodimerization, and induces transphosphorylation of tyrosine residues in the cytoplasmic domains which serves as docking sites for several adaptor molecular harboring SH2 domain or phosphotyrosine binding domain. These adaptor molecules recruit and activate downstream signaling molecules such as Ras/MAPK, phospholipase C-r, JAK-STAT molecules, NF-KB pathways through tyrosine- or serine/threnonine-phosphorylation. Among them, Ras /MAPK/ERK, PI3-K/akt and STAT pathways act as the major oncogenic signaling pathway. Overall, these receptors coupled with their ligands are key importance in human subtle balance in physiologically regulating multiple cellular processes, for example, in cellular proliferation and differentiation. Oncogenic receptors mutational activation and/or aberrant gene rearrangement are promiscuously interference with normal cell survival, anti-apoptosis and proliferation, and malignant initiation and progression. Others, in a special APL case, oncogenic pml/RARa fusion behave as a potent (constitutive) transcriptional repressor of RAR and retinoic acid signaling, inducing a differentiation blockage at promyelocytic stage which can be overcome with therapeutic doses of 9-cis retinoic acid or ATRA ligand (see in detail model, George Zhu, January 1991. Curr Pharm Biotechnol, 2013, 14: 849-858)^[2,6,8]. This is the classical model of retinoic acid action. This encourages receptor normal agonist, and oncogenic receptor antagonists (or inhibitors) target therapy.