Inhibitors of Growth Factor Receptor Tyrosine Kinases

The rationale to target growth factor receptors is compelling; they are frequently upregu-lated in human cancers and confer either more aggressive clinical behavior or are responsible for malignant transformation (1). The well-characterized drug targets in solid tumors are erbB1 (EGFR or HER1) and erbB2 (HER2 / neu), two proteins belonging to the erbB family, and also the c-kit/stem cell factor receptor (SCFR). ErbB1 is a 170-kD transmembrane glycoprotein that forms homo- (erbB1/erbB1) or heterodimers (erbB1/erbB2, erbB1/erbB3) with other members of the family upon binding with EGF or other ligands, including transforming growth factor-« (TGF-a) (65). The erbB2 is a 185-kD tyrosine kinase anchored to the cell membrane; although a ligand for erbB2 has not been identified, this protein is the preferred heterodimerization partner within the family (65). Gene amplification, mutation, and increased expression of the erbB members have been reported in glioblastomas, breast, lung, colon, bladder, and head and neck malignancies (65). The receptor tyrosine kinase (RTK) inhibitors, gefitinib and erlotinib, block the activation of the signal transduction pathway initiated by the RTK of erbBl, whereas the monoclonal antibodies, cetuximab and trastuzumab, target erbBl and erbB2, respectively (65). Treatment with these drugs results in clinically significant responses in patients with non-small cell lung cancer (NSCLC) [gefitinb, erlotinib (66)], colorectal cancer (cetuximab), and breast cancer (trastuzumab) (65). The activity of trastuzumab is dependent on gene amplification and overexpression of erbB2, whereas the role of target expression and/or activation of signal transduction pathway of erbBl is less clear (67). Resistance to EGF-RTK inhibitors and anti-erbBl monoclonal antibodies is likely to occur in tumors bearing the most common EGFR mutation, namely EGFRvIII (DEGFR or del2-7EGFR), which is characterized by the deletion of exons 2-7 in EGFR mRNA as a result of alternative splicing or gene rearrangements, and encodes for a truncated extracellular EGF-binding domain with ligand-independent constitutive activation (68).

Imatinib is an effective inhibitor of the c-kit/SCFR and platelet-derived growth factor receptor A (PDGFRA); this receptor is mutated and overfunctioning in a selected group of malignancies, particularly gastrointestinal stromal tumors (GIST). Activating mutations of c-kit gene, mostly involving exons 9 and 11, are present in up to 92% of the GISTs and are likely to play a critical role in the development of these tumors (69). In patients with GIST-harboring exon 11 c-kit mutations, the partial response rate was 83.5%, whereas patients with tumors containing an exon 9 mutation or no detectable mutations of c-kit or PDGFRA had partial response rates significantly lower (47.8% and 0.0%, respectively) (69). Finally, cells bearing the Asp816Phe, Asp816Tyr, and Asp816Val mutations in the kinase domain of c-kit are resistant to imatinib, whereas the Val560Gly mutant displays increased affinity for the drug (Fig. 5) (70).

Cure Your Yeast Infection For Good

Cure Your Yeast Infection For Good

The term vaginitis is one that is applied to any inflammation or infection of the vagina, and there are many different conditions that are categorized together under this ‘broad’ heading, including bacterial vaginosis, trichomoniasis and non-infectious vaginitis.

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