Oncogenes as anticancer drug targets

Cancer therapy directed at specific, frequently occurring molecular alterations in signaling pathways of cancer cells has been validated through the clinical development and regulatory approval in the recent years (6). An example of an approved therapeutic agent is Herceptin/trastazumab, a humanized antibody directed against the product ofthe HER2/ neu oncogene, which is amplified in approx 20% of advanced breast cancer and encodes a receptor tyrosine kinase. Another example is the small-molecule drug Gleevec/imatinib, which inhibits the BCR-ABL tyrosine kinase and the c-kit tyrosine kinase receptor, and is currently used for treatment ofchronic myelogenous leukemia and gastro-intestinal cancer.

It is anticipated that a wave of sophisticated "smart drugs" directed at activated or over-expressed oncogene products identified through genomic and proteomic techniques will fundamentally change the treatment of all cancers (6). Tumor suppressor genes obviously represent more difficult targets because their products are lost or inactive in tumors. However, their loss could be exploited via the resulting increased sensitivity to DNA-damaging treatments or recombinant viruses, for example (7-10). For several oncogenes, it was shown that they are not only involved in establishing the tumor, but that they are also necessary for maintaining the growth and proliferation of tumor cells; for example, conditional inactivation of c-MYC in an experimental c-MYC-induced tumor leads to differentiation oftumor cells (11). Subsequent reactivation ofthe conditional c-MYC allele induced apoptosis, suggesting that even transient therapeutic inhibition of c-MYC could lead to a significant tumor reduction and even complete regression (reviewed in ref. 12). Although a number of oncogenes, which might serve as potential target proteins for further development of targeted therapeutics, are known, there is a shortage of targets for most of the common cancers. In the case of breast cancer, therapy with the anti ErbB2-antibody Herceptin is restricted to approx 20% of the breast cancer patients who have detectable HER2 amplifications. Therefore, numerous efforts are ongoing to identify frequently occurring amplifications/mutations present in the remaining 80% of breast cancers.

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