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| |  Combination Therapy May Be Effective Against Some Non-Small Cell Lung Cancers BOSTON -- January 19, 2010 -- Even when their tumours are shrinking in response to therapy, some patients with non-small cell lung cancer (NSCLC) have a scattering of cancer cells that are undeterred by the drug, causing the tumour to resume its growth, according to a study published in the January issue of the journal Cancer Cell. The findings suggest that identifying such patients and treating them with a combination of drugs from the very start of therapy can produce longer remissions. The study involves NSCLC tumours which are driven by a mutation in the gene EGFR. Such tumours, which account for about 12% of all NSCLC cases in the United States, often recede when treated with a tyrosine kinase inhibitors. Pasi Jänne, MD, Dana-Faber Cancer Institute, and Jeffrey Engelman, MD, Massachusetts General Hospital, Boston, Massachusetts, found that some patients with EGFR-mutant lung cancers harbour a small number of tumour cells with an overabundance, or amplification, of MET even before treatment with a tyrosine kinase inhibitor, and that those few cells are enough to spark drug resistance. One of the triggers for resistance, the researchers found, is HGF, a ligand or ‘hook’ that activates the MET protein. When activated, HGF works through 2 entirely different channels to produce drug resistance, the authors reported. First, it can generate cell-growth signals through a protein called GAB1. Second, it expands the number of MET-amplified cancer cells, ensuring they will become the dominant type in the lung tumours. “Not only can HGF spur cell growth on its own, it can speed up the process by which MET-amplified cells emerge and take over the composition of the tumour,” said Dr. Jänne. In about 20% of NSCLC patients who are resistant to [erlotinib] the mechanism is amplification of MET, and in another 20% it may involve HGF. The findings suggest that patients whose NSCLC tumours harbour even a few MET-amplified cells prior to treatment would benefit from drugs that specifically target those cells, in combination with a tyrosine kinase inhibitor. Dr. Jänne noted that such drugs are already being studied in clinical trials. “Our findings provide a strong rationale for combination treatment strategies as initial therapies for some patients,” Dr. Jänne said. “This is especially the case in patients with evidence of pre-existing MET amplifications.” Dr. Engelman added, “A thorough analysis of a patient’s cancer prior to treatment can establish how it would ultimately develop resistance to therapy, allowing us to tailor treatment with greater precision to prevent resistance. For example, cancers found to harbour a small population of cells with pre-existing MET amplification will likely benefit from adding MET inhibitors to initial treatment. Those without such cells may not benefit, and these patients can avoid the added toxicity of MET inhibitors and instead focus on other strategies to prevent their cancers from becoming resistant.”
SOURCE: Dana-Farber Cancer Institute
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