Receptor Tyrosine Kinases As Target For Anticancer Therapy

Overexpression and/or structural alteration of RTKs' family members are often associated with human cancers, and tumor cells are known to use RTK transduction pathways to achieve tumor growth, angiogenesis, and metastasis. Thus, RTKs represent a pivotal cancer therapy target. Several small molecules acting as RTK inhibitors have been synthesized by pharmaceutical companies and are under clinical trials. Some are being analyzed in animal models or already have been successfully marketed. Cancer-homing toxins are a group of man-made cytotoxic molecules targeting cancer cells. These molecules contain toxins, natural or usually derivatives, connected to a cancer-homing module, such as a monoclonal antibody or growth factor or their derivatives.

SUGEN, Inc., a biopharmaceutical company, focused on the discovery and development of small-molecule drugs that target specific cellular signal transduction pathways. Recent reports indicate that several small-molecule inhibitors are being used against the ATP-binding site of c-Met, which may be the new standard up-front treatment for patients with SCLC. Geldanamycin, of the anisamycin antibiotic family, has been found to inhibit c-Met in SCLC cells by down-regulating the expression of certain cell-signaling proteins.24 This inhibition of c-Met RTK by Geldanamycin includes several tyrosine and serine/threonine kinases, as well as stress-related protein, HSP 90. Small peptides derived from the tail of the c-Met receptor also possess high affinity for the receptor, and after binding it they inhibit its activity.24 Additionally, they were was found to block HGF-mediated invasive growth by 50% in the A549 cell line, as determined by invasion, cell migration, and branching morphogenesis. The Grb2-associated binder (Gab1) has recently been identified as a multisubstrate adapter protein of the insulin-responsive substrate 1 family that associates with the c-Met receptor and mediates epithelial morphogenesis. Gabl is a potent inhibitor of HGF/SF-c-Met signaling pathways for cell survival and DNA repair downstream of PI3K.66'80

As mentioned earlier, 70% of SCLC express the kit receptor tyrosine kinase and its ligand, stem cell factor (SCF). Several studies determined that inhibitors of kit tyrosine kinase activity could have therapeutic efficacy in this disease. SCF-induced c-kit phosphorylation was found to be inhibited by PP2 (4-chlorophenyl-7-t-butyl-pyrazolo 3,4-d-pyrimidine) and STI571. When a small-cell lung cancer cell line (H526) was treated with STI571, SCF-mediated c-Kit activation was inhibited, as measured by decreased receptor tyrosine phosphorylation.71 This drug can inhibit the kinase activity of c-kit, but it has no effect on the related receptor tyrosine kinases c-Fms and Flk2/Flt3. Based on these investigations, clinical trials are underway for the role of STI571 in SCLC.

Currently, there are many potent tyrosine kinase inhibitors against EGFR. It is an important potential therapeutic target, and the small-molecule, orally superactive EGFR-tyrosine kinase inhibitor (ZD 1839) is currently under investigation as monotherapy in clinical trials in patients with a very advanced NSCLC. ZD1839 (up to 1000mg/day) has been studied in four open-labeled, multicenter, phase I studies involving patients with a variety of solid malignant tumors, including NSCLC.81-83 ZD1839 is already being used in clinics in combination with standard therapy for NSCLC, such as carboplatin and paclitaxel.

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