Researchers Uncover Mutated Genes Involved In Lung Cancer; One Affects Nonsmokers

Mutations in the epidermal growth factor receptor (EGFR) gene are present mainly in adenocarcinomas, the most common form of lung cancer found in smokers and non-smokers, as well in women and people under 45. These mutations have shown increased sensitivity to gefitinib (Iressa) and erlotinib (Tarceva), drugs targeting the gene.

To understand better the role of the EGFR mutation in the development of lung cancer, Dr. Gazdar and his colleagues analyzed tissue samplesfrom primary tumors of 519 patients in the United States, Japan, Taiwan and Australia. Mutations in the DNA of nonmalignant lung tissue from many of these patients and from other separate cancer tissues also were examined.

The researchers found mutations in the EGFR gene were much more common:

* in people with lung cancer who never smoked compared to smokers (51 percent vs. 10 percent, 85 of 166 nonsmokers vs. 35 of 353 smokers); * in adenocarcinomas compared to other lung cancers (40 percent vs. 3 percent, 114 of 289 adenocarcinomas vs. 6 of 230 other cancers); * in women compared to men (42 percent vs. 14 percent, 72 of 171 women vs. 48 of 348 men); * in patients of Asian ancestry compared to other ethnicities (30 percent vs. 8 percent, 107 of 361 Asians vs. 13 of 158 in other ethnicities).

Mutations in the KRAS gene - a gene in the EGFR signaling pathway - were found in8 percent of lung cancers but in none with the EGFR mutation. This mutation was more common in males, Caucasians, and current or former smokers.

As a result, it appears that two distinct molecular pathways are involved in formation of lung cancer, Dr. Gazdar said. The pathway in smokers involves KRAS gene mutations, while the pathway in people who never smoked involves EGFR gene mutations.

The next step is to move these findings toward development of better treatments for lung cancer, said Dr. Gazdar.

He and Dr. John Minna, director of the W.A. "Tex" and Deborah Moncrief Jr. Center for Cancer Genetics and the Hamon Center for Therapeutic Oncology Research and a contributing author, have established eight lung cancer cell lines that harbor several types of EGFR mutations and are now establishing another line from a patient who relapsed after initially responding well to the gefitinib drug.

"These lines will prove invaluable in understanding both the response to gefitinib and erlotinib and the mechanisms by which resistance eventually develops," Dr. Gazdar said. "The cell lines may help identify strategies to overcome this drug resistance that eventually develops in most responders."

A related study in the current issue of Cancer Research with Dr. Gazdar and his colleagues found that mutations in EGFR and HER2, another gene in the EGFR pathway that is associated with certain cancers, targeted the same patient subpopulations. The discovery that HER2 also is a mutation occurring mainly in tumors of people who never smoked suggests different pathways may be involved in lung cancer formation in smokers and nonsmokers.

"Our work is very important because if you have a mutation in the EGFR gene in the tumor, a patient likely will have a dramatic response to a relatively nontoxic once-daily oral therapy," Dr. Minna said. "The research has found these tumors can vary by several thousandfold on how sensitive they are to a drug," said Dr. Minna. "We also have been able to identify in advance a pattern of gene expression that tells whether a tumor is going to be resistant or sensitive to a particular drug. We want to be capable of examining a patient's tumor, profile each human gene and then select the best current therapy."

Dr. Minna and Dr. Jonathan Dowell, assistant professor of internal medicine, contributed to an editorial in the Feb. 24 issue of The New England Journal of Medicine commenting on a study headed by Dana Farber Cancer Research Center. Researchers there found a lung cancer that initially was very sensitive to gefitinib because of a mutation in the EGFR gene developed resistance to the drug because of a second EGFR mutation.

The enhanced understanding of EGFR and these mutations reported in the NEJM study will allow new drugs to be designed to combat these drug-resistant receptors, enabling effective second-line therapy to then be directed at the same target, Dr. Minna wrote.

Other UT Southwestern contributors to the JNCI study were Dr. Joachim Herz, professor of molecular genetics in the Center for Basic Neuroscience; Dr. Hisayuki Shigematsu and Dr. Masaharu Nomura, postdoctoral researchers, and Dr. Takao Takahashi, former postdoctoral researcher, all in the Hamon Center for Therapeutic Oncology Research. Researchers from UT M.D. Anderson Cancer Center in Houston also contributed, as well as investigators in Seattle, Japan, Taiwan and Australia.

Research was supported by grants from the NCI and Bristol-Myers Squibb.