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View the Table of Contents for the January 15 issue of Cancer Research
Page 379
Gefitinib is an ATP-competitive antagonist of the EGFR tyrosine kinase and has been approved for patients with advanced non-small cell lung cancer. To further explore potential modes of drug action, Brehmer et al. have established an efficient affinity purification technique that employs an immobilized gefitinib-like ligand for the isolation of cellular inhibitor targets. In addition to the EGFR, several other protein kinases such as the Ser/Thr kinase GAK were identified and characterized as sensitive gefitinib targets. Inhibition of GAK, a negative regulator of EGFR signaling, could potentially counteract the effect of gefitinib on EGFR-mediated tumor cell proliferation and survival.
Page 427
Studying a series of Li-Fraumeni syndrome (LFS) kindreds lacking mutations in the tumor suppressor gene TP53, Bachinski et al. identified linkage to a 4-cM region in 1q23 not previously implicated in LFS. Just as the identification of high-penetrance inherited cancer genes in breast cancer or colorectal cancer has provided considerable fundamental insights into many aspects of cancer genetics and biology, the eventual identification of this gene and its underlying mutation(s) should provide insight into genetic events that predispose to diverse tumor types associated with LFS. It may also further elucidate the role of TP53 and its molecular pathways in cancer.
Page 507
Although R-Ras is highly homologous to Ras proteins, its transforming activity is less compared to Ras. To address its biological functions, Jeong et al. have determined that active R-Ras increased adhesion but disrupted motility in breast epithelial cells by RhoA/Rho kinase pathway. Using H- and R-Ras hybrid constructs, they also demonstrated that the C-terminal region of R-Ras contains the specific signal for changes in motility and morphology. Disruption of motility may be responsible for the less transforming activity of R-Ras and even R-Ras, in some respects, might oppose oncogenic effects of transforming factors including Ras.
Page 605
The HIF-1 pathway is an increasingly important target for pharmacological intervention against solid tumors. To identify novel small-molecule inhibitors of the HIF-1 pathway, Tan et al. screened a 10,000-membered 2,2-dimethylbenzopyran combinatorial library with a cell-based assay. This screening led to the discovery of 103D5R, a compound which markedly reduced HIF-1α protein synthesis without affecting HIF-1α mRNA steady state levels and protein degradation. 103D5R is a lead molecule for a novel class of HIF-1 inhibitors that may evolve into new cancer chemotherapeutics.
Page 664
New pharmacological targets are needed to develop strategies to reduce the risks of cancer in smokers. Moraitis et al. first determined that cyclooxygenase-2 (COX-2) was overexpressed in the oral mucosa of active smokers versus never smokers and then attempted to elucidate the underlying mechanism. The results of in vitro studies indicated that tobacco smoke stimulated epidermal growth factor receptor (EGFR) tyrosine kinase activity leading, in turn, to enhanced transcription of COX-2. Because both COX-2 and EGFR have been implicated in carcinogenesis, these findings highlight the potential importance of COX-2 and EGFR as molecular targets for the chemoprevention of tobacco smoke-related malignancies of the aerodigestive tract.