The role of oncogenic kinases in human cancer (Review)

Abstract

Tumorigenesis in humans is a multistep process, which reflects genetic alterations that lead to cell transformation and malignancy. Cellular genes that are altered are normally involved in maintaining cell homeostasis by participating in signaling pathways tightly regulated to maintain the functional integrity of the cell. When these genes are altered they escape from the regulatory control and transmit signals that lead to the progressive conversion of normal cells into cancer cells. Oncogenic signals involve activation of kinases, which can be either a primary event when they are directly mutated in a tumor cell or a secondary event as recipients and mediators of oncogenic signals. Transmembrane (e.g. EGFR, PDGFR) or cytoplasmic (Src, Abl) tyrosine kinases are found mutated in a variety of human tumors. Cytoplasmic serine threonine kinases (Raf, Akt, Tpl-2) are also mutated or activated in several types of human malignancies. Kinases transduce signals that lead to cell proliferation or inhibition of programmed cell death by activating transcription factors (e.g. AP1, NFkappaB, Myc), inhibiting pro-apoptotic molecules (e.g. Bad, Bax), or they participate in deregulating the cell cycle control. Thus, kinases play a central role in oncogenesis rendering them putative targets for anti-cancer drug design.