Acquired resistance to chemotherapy is a major obstacle to successful cancer treatment. Understanding the mechanisms by which tumors become resistant to a particular agent is key to identifying new drugs or combination regimens. In an upcoming article in the international open-access journal PLoS Medicine, William Pao and colleagues (from the Memorial Sloan-Kettering Cancer Center in New York) shed light on what causes resistance to two recently approved lung cancer drugs.
The drugs are so-called kinase inhibitors and inhibit the epidermal growth factor receptor (EGFR) kinase molecule. Both of them, gefitinib (Iressa) and erlotinib (Tarceva), have shown therapeutic benefits in a subset of patients with lung cancer. Recent work has helped to understand why some patients respond and some don't: responsive tumors usually harbor activating mutations in the EGFR gene, which somehow make the tumors sensitive to treatment. Nearly all patients whose tumors initially respond to the drugs, however, eventually become resistant to the drugs and progress despite continued therapy.
In this study, the scientists examined tumors from six patients with non-small cell lung cancer who initially responded to gefitinib or erlotinib but subsequently relapsed. Tumors from all six patients carried activating mutations in the EGFR gene. In addition, in three out of the six cases, the resistant tumor cells carried an identical second mutation in the EGFR gene. Whereas the activating mutation was present in tumor cells before treatment with erlotinib or gefitinib, the second mutation was not found in pre-treatment biopsies from these patients, nor in over 150 lung cancer samples from patients who had not been treated with either drug. Additional cell culture studies supported the notion that the secondary mutation causes resistance to gefitinib or erlotinib. It is clear, though, that this is only one of several resistance mechanisms, because in the three other cases resistance occurred in the absence of the second mutation. What caused the resistance in those tumors is not known.
All kinases share some common features, and a resistance mutation very similar to the one identified here has also been found in other kinase genes from tumors with acquired resistance to imatinib, another kinase inhibitor. As Gary Gilliland and colleagues point out in an accompanying Perspective article, the initial identification three years ago of resistance mutations against imatinib led to the rapid development of alternative kinase inhibitors that work even against tumors with the resistance mutation. Similarly, the results by Pao and colleagues should help researchers develop second generation drugs for lung cancer.
Citation: Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, et al. (2005) Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. 2(3): e73.
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