New Clues to Lung Cancer Drug Resistance

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Researchers have new insight into why some lung cancer patients stop responding to the drugs Tarceva (erlotinib) and Iressa (gefitinib).

These drugs stop the growth of certain cancers by targeting a signaling molecule vital to the survival of those cancer cells. They are effective in about 10 percent of patients with non-small cell lung cancer (NSCLC). In this type of cancer—which often occurs in patients with no history of smoking—malignant cells carry mutations in a gene that encodes the epidermal growth factor receptor (EGFR).

"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. This is different from primary resistance, which means that the drugs never work at all,” Dr. Vincent A. Miller, a thoracic oncologist at New York’s Memorial Sloan-Kettering Cancer Center (MSKCC) and one of the study’s two lead authors, said in a prepared statement.

To find out why these cancers become drug-resistant, the researchers followed six NSCLC patients who’d been treated with either Tarceva or Iressa and later developed secondary resistance. They analyzed tumor samples taken from the patients at various points before and during treatment.

In three of the six patients, tumors continued to grow despite continued therapy. These tumors were found to contain a second mutation in the EGFR gene. Further research revealed this second mutation conferred drug resistance to the EGFR mutant genes that would otherwise be sensitive to Tarceva and Iressa.

The study appears in the Feb. 22 issue of PLoS Medicine.

In a prepared statement, senior author Dr. Harold Varmus, president of MSKCC, said this second mutation is similar to gene variants researchers have come across before. That knowledge may provide some hope to patients whose cancers have grown resistant to Tarceva or Iressa, he added.

The mutation is “analogous to a mutation that makes other kinds of tumors resistant to another targeted therapy, imatinib mesylate (Gleevec),” he said. Gleevec is a drug that’s proven very effective in fighting a form of leukemia and other cancers caused by mutations in signaling enzymes like EGFR.

“Acquired resistance to Gleevec is a well-known problem, and understanding its molecular cause has led to the design of other drugs that overcome that resistance,” Varmus pointed out.

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