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Two Studies From Separate Research Groups Identify Acquired Mutations that Halt Response to Iressa, Tarceva

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In a subset of cancer patients, the target for the non-small cell lung cancer drugs Iressa and Tarceva mutates in a way that blocks the drug without inhibiting growth-factor binding, according to two separate studies published this week.

The coincidence is “great,” said Memorial Sloan-Kettering Cancer Center researcher William Pao, who co-authored the study with Harold Varmus, president of the cancer center. “Two independent groups came up with the same thing, so the likelihood is that this is a real thing — rather than an artifact from the lab. It’s always nice when someone independently gets the same results,” he said.

In a recent issue, Pharmacogenomics Reporter featured the work of one of the two groups — the one based at Sloan-Kettering — which described the primary resistance to Iressa and Tarceva of some non-responders to the drug [see Pharmacogenomics Reporter, 2/3/2005]. The current research by that group, along with another from Beth Israel Deaconess Medical Center, explains the acquisition of secondary resistance to the drugs and points to the possible development of new compounds to overcome that resistance.

“Instead of not responding at all, these patients had their tumors shrink and benefited from the drugs,” said. Pao. “But then they eventually stopped responding, and their tumors grew back,” he said.

The drugs Iressa and Tarceva are effective in stopping the growth of tumors that have a particular mutation in the EGFR gene, which produces the protein targeted by the drugs.

The MSKCC researchers re-biopsied patients who stopped responding to Iressa or Tarceva, and sequenced the tumors’ EGFR gene. Three of Pao’s patient group of six showed a new mutation in the EGFR gene that seems to have blocked drug binding, he said. “It’s right there [in the gene sequence responsible for the protein region] where the drug is supposed to bind,” said Pao.

The new mutation was present in tumor samples that continued to grow during drug treatment, but not in biopsy samples of the patients’ original tumors, he said. “We did biochemical and cell-line studies that seemed to show that, at least in the laboratory, this mutation confers resistance to Iressa and Tarceva,” he added.

The new mutation, however did not appear to interfere with binding of epidermal growth factor, which the tumor cells require for growth, said Pao. “In fact, it probably still signals,” he said. “It’s helpful, because then we can understand what the problem is. We can try to design new drugs that still bind in that pocket that cannot be blocked by this resistance mutation,” he said.

The situation is very similar to that found in certain chronic myelotic leukemia tumor cells that stop responding to Gleevec, said Pao. In those cells, a mutation in Gleevec’s target signaling molecule ABL prevents drug binding, he said. “Our mutation — the one that we found — is very similar to ones found in ABL … so it may be a more common mechanism, and a problem with new targeted agents, like these kinase inhibitors,” he added.

“Our paper has a [PCR-based] way to simply test for the second mutation,” said Pao.

— CW

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