University Of Florida Researchers Identify A Protein That May Induce Drug Resistance In Lung Cancer Cells

The findings are a first step toward better understanding the underlying molecular mechanisms that enable these cancer cells to survive and strengthen, UF researchers reported Sunday (3/25) at the annual meeting of the American Association for Cancer Research in New Orleans.

While chemotherapy may prolong survival for many patients, ultimately it is not likely to cure the disease, especially for those with a form known as small-cell lung cancer.

“The big problem with this type of cancer is that patients respond fairly well to chemotherapy and radiation after diagnosis, but within a two- to three-year period most relapse,” said Lei Xiao, an assistant professor of anatomy and cell biology at UF’s College of Medicine and the UF Shands Cancer Center. “Those patients, if previously treated with chemotherapy, will have cancer that is resistant to treatment. Instead, the lung cancer keeps growing.

“We’re interested in why lung cancer is so deadly and how to overcome the problem of what’s considered to be very aggressive malignant behavior,” she added. “We want to know more about the phenomenon of why the relapsed patient becomes resistant. We’d like to understand the process and eventually find a way to stop or correct the process and help the patient again respond to therapy.”

Lung cancer is the most common cancer-related cause of death, according to the American Lung Association. An estimated 164,100 new cases were diagnosed in the United States last year alone. Meanwhile, more than 150,000 lung cancer patients died in 2000. Lung cancer typically appears in one of two forms that vary genetically: small cell or non-small cell.

Small-cell lung cancer accounts for about a fourth of all new lung cancer cases, Xiao said. It is very aggressive and often has metastasized to other parts of the body by the time the patient’s disease has been diagnosed.

The statistics are grim: Although more than 80 percent of patients respond to treatment at first, the five-year survival rate for patients whose cancer recurs is only 3 percent to 8 percent.

“Even though we can temporarily induce remission or at least decrease the size of the cancer, we don’t actually completely cure lung cancer because of this problem of drug resistance,” said Dr. Eloise Harman, a professor of medicine and chief of the division of pulmonary medicine at UF’s College of Medicine. “It’s been a big problem.”

Previous clinical and laboratory studies have suggested that drug resistance in patients with small-cell lung cancer develops when the cancerous cells actually transform into the non-small cell type, a form notorious for failing to respond to chemotherapy. But just how that happens has been a mystery.

Now UF researchers have linked a protein known as protein kinase C-epsilon, or PKC-epsilon for short, to this transition. While the gene for the protein does exist naturally in small-cell lung cancer cells, it normally is inactive, so the protein is not produced.

In laboratory cultures of small-cell lung cancer, scientists introduced the gene and discovered that the cells began producing the protein and became resistant to two common chemotherapy drugs, etoposide and doxorubicin, at various concentrations. Cells that expressed the protein were more likely to survive, in part because the protein disrupted the process of programmed cell death, which tells cells in the body when their natural lifespan is over.

“We induced the expression of PKC-epsilon, and we could see cells change their behavior in response to the chemotherapy drugs we administered,” said Xiao, whose research is funded by a four-year, $800,000 grant from the National Cancer Institute. “PKC might be one of the candidates that does something regarding the development of a drug-resistant phenotype.”

Researchers say that linking expression of the protein with drug resistance is just the first step in understanding the potentially complex physiologic processes that influence drug resistance, and they are years away from developing any kind of treatment for lung cancer patients.

Xiao said UF researchers would like to know more about how the gene responsible for the protein’s function signals it to act. Someday clinicians could target the gene and prevent it from relaying its harmful message, or find improved ways of targeting cancer cells using the cells’ own natural defense mechanisms to induce a kind of genetic suicide, while sparing healthy cells.

Eventually, scientists might be able to use the protein as a marker to identify patients prone to drug resistance, and treatments could be tailored accordingly, Xiao said.

“This research is trying to look at what the underlying molecular mechanisms are for developing chemotherapy drug resistance in small-cell lung cancer,” Harman said. “So presumably if the mechanism of resistance to chemotherapy drugs can be found we’ll be able to develop better treatments for lung cancer. The thought has been that cells undergo some type of genetic changes that allows them to resist cancer drugs, and I think that this paper demonstrates that’s actually the case. This sort of research might open the door to novel therapy for lung cancer.”

Dr. Mark R. Green, the Gilbreth professor of clinical oncology at the Medical University of South Carolina, said if the association between the protein and drug resistance proves to be a widespread phenomenon, “it could be the focus of wider research and clinical applications.”