gpawelski Posted June 14, 2006 Share Posted June 14, 2006 Tarceva is a targeted therapy, in that it halts the growth of certain cancers by zeroing in on a signaling molecule critical to the survival of those cancer cells. The drug is effective in about 10-15% of patients with non-small cell lung cancer. The drug works specifically in patients whose cancers contain mutations in a gene that encodes the epidermal growth factor receptor (EGFR). Lung cancer patients with these mutations are often people who have never smoked. Although this targeted therapy is initially effective in a subset of patients, the drug can eventually stop working, and the tumor begins to grow again. This is called acquired or secondary resistance. This is different from primary resistance, which means that the drug never worked at all. The change of a single base in DNA that encodes the mutant EGFR protein has been shown to cause drug resistance. The T790M mutation has been thought to cause resistance by sterically blocking binding of small molecule tyrosine kinase inhibitors such as Iressa and Tarceva. Drug resistance evolves by multiple mechanisms. Initially, tumors have the kinds of mutations in the EGFR gene that were previously associated with responsiveness to these drugs. But, sometime tumors grow despite continued therapy because an additional mutation in the EGFR gene, strongly implies that the second mutation was the cause of drug resistance. Biochemical studies have shown that this second EGFR mutation (T790M), which was the same as before, could confer resistance to the EGFR mutants normally sensitive to these drugs. It is especially interesting to note that the mutation is strictly analogous to a mutation that can make it tumor resistant. Non-small cell lung cancer makes up about 80 percent of all lung cancers. Mutations in a gene called KRAS, which encodes a signaling protein activated by EGFR, are found in 15 to 30 percent of these cancers. The presence of a mutated KRAS gene in a biopsy sample is associated with primary resistance to these drugs. Tumor cells from patients in a study who developed secondary resistance to Tarceva after an initial response on therapy did not have mutations in KRAS. Rather, these tumor cells had new mutations in EGFR. This further indicates that secondary resistance is very different from primary resistance. All the EGFR mutation or amplification studies can tell us is whether or not the cells are potentially susceptible to this mechanism of attack. They don't tell you if Tarceva is better or worse than Iressa or some other drug which may target this. There are differences. The drug has to get inside the cells in order to target anything. EGF-targeted drugs are poorly-predicted by measuring the ostansible target EGFR, but can be well-predicted by measuring the effect of the drug on the 'function' of live cells. A cell-based targeted therapy profile includes analysis of the following targeted drugs: Tarceva, Iressa, Nexavar, and Sutent. Literature Citation: PLoS Medicine, February 22, 2005 Eur J Clin Invest 37 (suppl. 1):60, 2007 Quote Link to comment Share on other sites More sharing options...
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