Anticancer drug targets: growth factors and growth factor signaling.

Signaling mechanisms that drive cell proliferation are closely associated with tumor malignancy. Components of these pathways, encoded by some of the very first oncogenes identified, include the PDGF-like ligand Sis, the tyrosine kinases Src and HER-2/c-Neu (HER-2), and the GTP-binding switch Ras. The study of communication by these oncoproteins has identified a complex array of intracellular circuits. In some cancers, mutations in key components lead to constitutive activation of these pathways; this activation is associated with the proliferative properties of the tumor cells. In this Perspective, I provide a broad overview of a growth factor signal transduction system, with a focus on those points that have been translated to drugs or clinical candidates. Due to editorial restrictions limiting the number of reference citations, much of the clinical data gleaned from abstracts is not listed in the references. Instead, the reader is directed to the 1999 Proceedings of the American Society of Clinical Oncology and the 1999 Proceedings of the AACR-NCI-EORTC International Conference. Signaling pathways are initiated with the binding of a ligand, such as PDGF, EGF, EGF-like ligands (e.g., TGF-α and amphiregulin), or IGF, to its cognate transmembrane receptor (1). Ligand binding induces the dimerization of receptor subunits, promoting autophosphorylation of the receptor and recruiting a variety of intracellular docking proteins (such as Grb2, Shc, and Nck) to the plasma membrane. These docking proteins create a molecular scaffold from which subsequent signals emanate. For example, the guanine nucleotide exchange factor Sos binds to Grb2, which in turn interacts with the Ras protein. Ras serves as a molecular switch in the plasma membrane that alternates between an inactive GDP-bound state and an active GTP-bound state. Normally, Ras is bound to GDP because of the abundance of GTPase-activating protein and neurofibromin, which both suppress Ras function. However, upon recruitment of Sos to the membrane, Sos binds Ras-GDP and facilitates release of GDP. In cells, the nucleotide GTP is about 10-fold more abundant than GDP; GTP binds to Ras by mass action. Ras-GTP adopts a conformation that permits interaction with downstream targets called effector molecules. These effectors include the protein kinase Raf, which activates the MAP kinase cascade; GTPase-activating protein, which links Ras to the Rho/Rac pathway; and phosphoinositide (PI) 3′-kinase and Ral–guanine nucleotide dissociation stimulator (Ral-GDS), which activate lipid pathways (2). The dysregulation of these signals in tumor cells leads to multiple cellular changes, including alterations in DNA synthesis, lipid metabolism, cellular morphology, cell adhesion properties, and gene expression. In the broadest sense, the study of signaling mechanisms has already yielded therapeutic agents in the treatment of cancer, as evidenced by antiestrogens, antiandrogens, agonists of gonadotropin-releasing hormone, and stem cell growth factors, for example. However, research into oncoproteins that function within the signal transduction system is only beginning to be applied in the clinic. Therapeutic approaches of interest include tools such as mAbs against the extracellular domain of receptors, oligonucleotides that are antisense to key target proteins, and small molecule inhibitors of enzymes (Table ​(Table11). Table 1 Examples of inhibitors of growth factor signaling for cancer treatment