Unrelated protein activated to bypass blocked growth signal, new treatment approach suggested

Pasi A. Jänne, MD, PhD

An international research team, led by investigators from the Massachusetts General Hospital (MGH) Cancer Center and Dana-Farber Cancer Institute, has found a new way that some lung tumors become resistant to treatment with targeted therapy drugs like Iressa and Tarceva. Their report, which will appear in the journal Science and is receiving early online release, describes a totally new resistance mechanism that may apply to many types of cancer. It also suggests a treatment strategy for patients with these resistant tumors.

"We found that, for about 20 percent of patients with tumors that become resistant to Tarceva or Iressa, resistance is caused by the genetic activation of an oncogene that is not the normal target of the drug, which is something that has never been seen before," says Jeffrey Engelman, MD, PhD, scientific director of the MGH Center for Thoracic Cancers, the paper's lead author.

"Importantly, we also identified a potential new way to treat these resistant tumors with combination therapy directed against both protein targets," adds Pasi A. Jänne, MD, PhD, of the Lowe Center for Thoracic Oncology at Dana-Farber, the study's senior author.

Drugs like Iressa (gefitinib) and Tarceva (erlotinib) are used to treat advanced non-small-cell lung cancer (NSCLC), the leading cause of cancer deaths in the U.S. They act by blocking the epidermal growth factor receptor (EGFR), a molecule on the surface of cancer cells. In 2004, research teams from MGH and Dana-Farber found that only tumors in which the EGFR gene has been mutated in a way that magnifies the cells' response to the growth factor, a process that fuels tumor growth, were sensitive to treatment with these drugs.

Although tumors that respond to EGFR inhibitors do so rapidly and dramatically, eventually the tumors become resistant and resume growing. About half the time, a secondary mutation that interferes with the drugs' binding to the receptor develops within the EGFR gene. A new group of so-called irreversible EGFR inhibitors that permanently bind to the protein are currently being tested in clinical trials. But what leads to other cases of resistance has been unknown, and the current study was designed to discover additional mechanisms.

To do so, the investigators modeled in a laboratory setting what happens in lung cancer patients; they used a line of NSCLC cells with the sensitizing EGFR mutation and created a cell line resistant to treatment with Iressa. In a number of experiments comparing the resistant line with still-sensitive cells, they focused on the cell signalling pathway controlled by EGFR. In earlier research, Engelman and colleagues had found that the growth signal that starts with EGFR works through a related protein called ERBB3.

The current study showed that, in some of the resistant cells, ERBB3 is activated by amplification of a different oncogene called MET, in essence bypassing the blockage of EGFR. Analysis of samples from patients whose tumors became resistant after initially responding to Iressa revealed that MET was amplified in resistant samples from 4 of 18 patients. Although treating resistant cell lines with either Iressa or a MET inhibitor did not stop tumor growth, treatment with both agents did induce cell death.

"This method of reactivating the EGFR signalling pathway with MET may be a common resistance mechanism in other therapies that target receptors of the ERBB family, which are used against breast cancer, colon cancer, head and neck cancer, and the brain tumor glioblastoma multiforme," says Jänne, who is an assistant professor of Medicine at Harvard Medical School (HMS).

"Our results suggest that, when patients' tumors become resistant, repeat biopsies to identify which resistance mechanism is involved will be critical and could help us develop effective therapies for those resistant tumors," adds co-author Lewis Cantley, PhD, of the Beth Israel Deaconess Medical Center.

To that end, the investigators are working on a research protocol for combined treatment with FDA-approved EGFR inhibitors and with MET inhibitors, which are in preapproval trials against other types of cancer. They also plan to analyze a larger number of resistant samples to get a clearer idea of the frequency of this resistance mechanism.

Additional co-authors of the Science report are Kreshnik Zejnullahu, Joon Oh Park, MD, PhD, Xiaojun Zhao, PhD, Alison Holmes, Andrew Rogers and Bruce Johnson, MD, of Dana-Farber; Tetsuya Mitsudomi, MD, and Takayuki Kosaka, MD, Aichi Cancer Center Hospital, Nagoya, Japan; Youngchul Song and Christopher-Michael Gale; Courtney Hyland, Neal Lindeman, MD, and Charles Lee, PhD, Brigham and Women's Hospital; James Christensen, PhD, Pfizer Global Research and Development; Federico Cappuzzo, MD, Instituto Clinico Humanitas, Rozzano, Italy; and Tony Mok, MD, Chinese University of Hong Kong. The study was supported by grants from the National Institutes of Health, including the National Cancer Institute; the American Cancer Society, the American Association for Cancer Research; the International Association for the Study of Lung Cancer; and the Italian Association for Cancer Research.

Massachusetts General Hospital (www.massgeneral.org), 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 nearly $500 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, transplantation biology and photomedicine.

Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), a designated comprehensive cancer center by the National Cancer Institute.