"This discovery will help us significantly improve the treatment of many lung cancer patients and is also an important next step in the molecular targeting of cancer drugs," says Daniel Haber, MD, PhD, director of the MGH Cancer Center and senior author of the NEJM paper. "We're hopeful that what we have learned will eventually lead to more new drugs that will target tumor-specific mutations without affecting normal tissues."
Iressa was approved a year ago for the treatment of advanced non-small-cell lung cancer (NSCLC), a tumor that is particularly difficult to treat and is the leading cause of cancer deaths in the U.S. In a major clinical trial Iressa caused tumors to shrink significantly in only 13.6 percent of patients, but some of those responses were rapid and dramatic. As a result, the FDA approved the drug because there are no other treatment options for NSCLC patients for whom standard chemotherapy has failed.
Iressa acts by disabling the epidermal growth factor receptor (EGFR) on the surface of lung cancer cells, halting a sequence of signals that can lead to the uncontrolled growth characterizing a malignant tumor. In their search for an answer to why the drug worked so well for some NSCLC patients but was of no assistance to others, the MGH team screened tumor samples from MGH patients who participated in the Iressa clinical trial to search for mutations in the EGFR gene.
Initial analysis found mutations affecting the same area (the ATP cleft of the kinase domain) of the receptor protein in eight of nine patients that had responded to Iressa, but no EGFR mutations were seen in tumors from seven patients who did not respond. In addition, many of the patients whose tumors responded to Iressa were of a subtype of NSCLC called bronchoalveolar cancer. Subsequently the researchers analyzed samples from 25 other NSCLC patients who had not been treated with Iressa. Two of those samples had mutations identical to ones found in Iressa-responding patients, and they were both bronchoalveolar tumors. Many samples from several other types of cancer were also studied, but none had similar EGFR mutations, indicating that they only are important in a particular subset of cancers.
To determine the effect of these mutations, the MGH team developed cultures of cells expressing two of the mutated receptor proteins. Compared with cells expressing the normal receptor, those with mutant EGFR responded much more powerfully to addition of growth factor, with a two- to three-fold increase in activation. In addition, receptor activation persisted six times longer in the mutant receptors than in cells with normal receptors.
Since most of the mutations identified in this study affect the area of the receptor targeted by Iressa, the researchers measured receptor activation in cells treated with various doses of the drug. They found that the mutated receptors were 10 times more sensitive to being inhibited by Iressa than were normal receptors.
"Understanding these mutations has helped us define the molecular basis of a type of lung cancer that relies on a particular signalling pathway which can be blocked," says Haber, a professor of Medicine at Harvard Medical School (HMS). "In addition, these mutations are unprecedented in that they increase proliferation of tumor cells while simultaneously making them more sensitive to drug treatment."
Thomas Lynch, MD, director of the MGH Thoracic Oncology Center and a co-lead author of the NEJM paper, says, "These findings will help determine which patients will benefit from Iressa and which should not receive it. In addition, if we know that a patient is likely to respond, we might be able to start treatment earlier with this drug that is more effective and has fewer side effects than standard chemotherapy." Lynch is an HMS associate professor of Medicine.
While there is currently no commercial test to screen tumor samples for this mutation, the MGH researchers are working to insure rapid development of a test based on this discovery, for which a patent has been applied. They also are setting up clinical trials of treatment plans based on screening for the identified EGFR mutations and hope to initiate studies involving treatment of early-stage tumors and as an adjunct to surgical tumor removal. Additional follow-up studies could help develop similarly targeted therapies against other tumors.
The report's other lead authors are Daphne Bell, PhD, and Raffaella Sordella, PhD, of the MGH Cancer Center. Additional co-authors are Sarada Gurubhagavatula, MD, Ross A. Okimoto, Brian W. Brannigan, Patricia L. Harris, Sara M. Haserlat, Jeffrey G. Supko, PhD, Frank G. Haluska, MD, PhD, David N. Louis, MD, David C. Christiani, MD, and Jeff Settleman, PhD, also of the MGH Cancer Center. The study was supported by grants from the National Institutes of Health, the Doris Duke Charitable Foundation, the Sandler Family Foundation, the Cole-Angelus Fund, Romaine Fund, and Sue's Fund for Lung Cancer Research.
The MGH Cancer Center is the largest provider of cancer care in New England and is a member of Dana-Farber/Harvard Cancer Center, which coordinates research collaborations throughout HMS.
Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $400 million and major research centers in AIDS, cardiovascular research, cancer, cutaneous biology, medical imaging, neurodegenerative disorders, transplantation biology and photomedicine. In 1994, MGH and Brigham and Women's Hospital joined to form Partners HealthCare System, an integrated health care delivery system comprising the two academic medical centers, specialty and community hospitals, a network of physician groups, and nonacute and home health services.