Mer or Axl receptor tyrosine kinase inhibition promotes apoptosis, blocks growth and enhances chemosensitivity of human non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is a prevalent and devastating disease that claims more lives than breast, prostate, colon and pancreatic cancers combined. Current research suggests that standard chemotherapy regimens have been optimized to maximal efficiency. Promising new treatment strategies involve novel agents targeting molecular aberrations present in subsets of NSCLC. We evaluated 88 human NSCLC tumors of diverse histology and identified Mer and Axl as receptor tyrosine kinases (RTKs) overexpressed in 69% and 93%, respectively, of tumors relative to surrounding normal lung tissue. Mer and Axl were also frequently overexpressed and activated in NSCLC cell lines. Ligand-dependent Mer or Axl activation stimulated MAPK, AKT and FAK signaling pathways indicating roles for these RTKs in multiple oncogenic processes. In addition, we identified a novel pro-survival pathway-involving AKT, CREB, Bcl-xL, survivin, and Bcl-2-downstream of Mer, which is differentially modulated by Axl signaling. We demonstrated that short hairpin RNA (shRNA) knockdown of Mer or Axl significantly reduced NSCLC colony formation and growth of subcutaneous xenografts in nude mice. Mer or Axl knockdown also improved in vitro NSCLC sensitivity to chemotherapeutic agents by promoting apoptosis. When comparing the effects of Mer and Axl knockdown, Mer inhibition exhibited more complete blockade of tumor growth while Axl knockdown more robustly improved chemosensitivity. These results indicate that Mer and Axl have complementary and overlapping roles in NSCLC and suggest that treatment strategies targeting both RTKs may be more effective than singly-targeted agents. Our findings validate Mer and Axl as potential therapeutic targets in NSCLC and provide justification for development of novel therapeutic compounds that selectively inhibit Mer and/or Axl.

Chemoprevention of lung cancer--from biology to clinical reality.

Lung cancer is the commonest cause of cancer death in developed countries and throughout the world. Cigarette smoking is the main risk factor for lung cancer and ex-smokers today comprise approximately 50% of all new lung cancer cases. Chemoprevention builds on the concepts of field of cancerization and multistep carcinogenesis and can be defined as the use of natural or chemical compounds to prevent, inhibit or reverse the process of carcinogenesis. So far, chemoprevention studies in lung cancer have failed to reduce lung cancer mortality. New developments in biotechnology have made it possible to define more accurately high-risk populations, make earlier diagnosis possible, and allow more specific targeted therapies to be developed. Both the development and validation of biomarkers, for the selection of high-risk study populations and for response evaluation in chemoprevention studies, are important for the faster turnover of studies evaluating new agents. This article reviews the current status and describes the perspectives for new approaches in the chemoprevention of lung cancer.

Evaluation of 2-(3-aminobenzamido)-2-deoxy-D-glucose as a radiosensitizer.

PURPOSE: 3-Aminobenzamide (3-AB), an inhibitor of poly(adenosine diphosphate [ADP]-ribose) synthetase, functions as a radiosensitizer in several human tumor cell lines. 2-(3-AB)-2-deoxy-D-glucose (3-AB-G) was designed to increase preferentially the intracellular concentration of the drug in tumor cells. Both the toxicity and effectiveness of 3-AB-G as a radiosensitizer were determined. MATERIALS AND METHODS: The toxicity of 3-AB-G was measured in HeLa and Chinese hamster ovary cells. The radiosensitizing effect of 3-AB-G was determined for both cell lines. RESULTS: 3-AB-G was not toxic to cells at concentrations of 10 mmol/L or less. 3-AB-G did not alter cell survival after irradiation. CONCLUSION: 3-AB-G was not an effective radiosensitizer for the cells tested. Coupling 2-deoxyglucose to 3-AB may block the uptake of the inhibitor into the cell by altering the ability of the receptor to recognize the molecule or may interfere with the specificity of the inhibitor for poly(ADP-ribose) synthetase.