Tarceva (erlotinib) and Iressa (gefitinib) are so-called targeted therapies, in that they halt the growth of certain cancers by zeroing in on a signaling molecule critical to the survival of those cancer cells. The two drugs are effective in about 10% of US patients with non-small cell lung cancer (NSCLC).
Previous work from the researchers at Memorial Sloan-Kettering Cancer Center (MSKCC) and from groups at Harvard Medical School showed that the two drugs work specifically in patients whose cancers contain mutations in a gene that encodes the epidermal growth factor receptor (EGFR). The MSKCC team has also shown that lung cancer patients with these mutations are often people who have never smoked.
“Although these targeted therapies are initially effective in this subset of patients, the drugs eventually stop working, and the tumors begin to grow again. We call this acquired or secondary resistance,” said Dr Vincent Miller, a thoracic oncologist at MSKCC and one of the study’s two lead authors. “This is different from primary resistance, which means that the drugs never work at all.”
The study involved six patients who had received treatment with gefitinib or erlotinib and who later developed acquired resistance. In three of the six patients, the researchers found that tumors that grew despite continued therapy had an additional mutation in the EGFR gene, strongly implying that the second mutation was the cause of drug resistance.
Further biochemical studies showed that this second EGFR mutation, which was the same in all three tumors, could confer resistance to the EGFR mutants normally sensitive to these drugs.
“It is especially interesting that the mutation we found is strictly analogous to a mutation that makes other kinds of tumors resistant to another targeted therapy, imatinib mesylate (Novartis’ Gleevec),” said Harold Varmus, president of MSKCC and senior author of the study. “Acquired resistance to Gleevec is a well-known problem, and understanding its molecular causes has led to the design of other drugs that overcome that resistance.”
The scientists are now looking into other possible reasons for gefitinib or erlotinib to stop working and hope to identify mutations in other potential cancer-causing genes.