Two designer cancer drugs differed dramatically in a laboratory test comparing their ability to shut down a mutant, overactive growth signal in lung cancer cells, reports a team headed by scientists at the Dana-Farber Cancer Institute.
Although both drugs killed cells containing a normal but overactive EGFR (epidermal growth factor receptor) molecule, only gefitinib (Iressa) killed lung cancer cells containing a mutated EGFR molecule. The monoclonal antibody drug cetuximab (Erbitux) had little effect on the mutant signal, evidently because it strikes at a different part of the EGFR molecule.
Reporting in the Aug. 17 issue of the Journal of the National Cancer Institute, the researchers say that the divergent results add to growing evidence that mutations in the targets of designer drugs critically influence their effectiveness. Erbitux is an effective inhibitor of EGFR signals in colorectal cancer, which involves a normal, not mutant, EGFR molecule.
"We now know of several groups of patients who benefit from therapy targeted at EGFR," says Pasi A. Janne, MD, PhD, of Dana-Farber, and a senior author of the paper. "Those with EGFR mutations will benefit from Iressa or Tarceva (erlotinib), while another group, without EGFR mutations, will benefit from Erbitux."
The lead author is Toru Mukohara, MD, and the senior authors are Bruce E. Johnson, MD, and Jänne, all of Dana-Farber.
Iressa and Erbitux both are designed to squelch the overexpressed, or overactive, EGFR signal that spurs growth in several types of cancer. In some forms of the disease, including lung cancer of the non-small-cell type, and colorectal cancer, the abnormal signals are generated by a normal EGFR molecule. In a small percentage of patients with non-small-cell lung cancer (NSCLC), the overactivity stems from a mutant EGFR protein: those patients tend to have a better outlook, and Iressa and Tarceva are particularly effective for them.
Mukohara and his colleagues wanted to determine whether Erbitux might be another option for NSCLC patients who carry the EGFR mutation. To test this idea, they treated lung cancer cell lines in the laboratory with Iressa and with Erbitux. They reported that both drugs blocked the excess signals in cells with normal EGFR, but only Iressa was significantly effective in those carrying a mutant EGFR.