Newly-described Route To Cancer Solves A Mystery In Lung Cancer

In the May issue of Cancer Research, Advances in Brief, the investigators report that protective proteins made by FUS1 are, in fact, normal, but that a critical modification that should take place after they are produced does not - and this renders the proteins inert.

Specifically, they found the defect is in a common cell process known as "myristoylation" that occurs when chains of fatty acids hook on to newly-minted proteins, which allows them to stick to the oily surface of the cell membrane.

In this case, the fatty acids don't attach on to the FUS1 protein, for reasons that are not understood, and the non-functional proteins are quickly broken apart inside the cell. Without FUS1 protein, cells cannot self destruct if damaged, thus cancer development can proceed unchecked.

This is the first time that myristoylation has been fingered as a potential root cause of cancer, say the researchers.

"Most genetic mechanisms for causing cancer include mutations that make gene products overactive or inactive. That's not the case here," says the study's senior author, Lin Ji, Ph.D., assistant professor in the Department of Thoracic & Cardiovascular Surgery Research. "This is a novel mechanism, a completely new way of disabling a tumor suppressor protein."

Loss of functional FUS1 "is certainly one of the earliest changes that occurs in lung cancer, and it likely happens in other cancers, such as breast and kidney, where the gene is known to be a target for inactivation," says co-author Jack Roth, M.D. chair of the Department of Thoracic & Cardiovascular Surgery.

Roth says the study suggests two potential therapeutic strategies. One would be to "reactivate myristoylation in tumor cells to restore their normal function," he says. The other is gene therapy to flood the tumor with active FUS1 genes - a phase I clinical trial currently under way at M. D. Anderson Cancer Center.

In order to design corrective treatments, Roth, Ji, and a team of researchers have been working for years to piece together a picture of what happens to a cell in the earliest stages of lung cancer. For example, they found that the p53 tumor suppressor gene was missing or altered in most lung cancer cells and that the gene could be successfully replaced. Clinical trials of p53 gene therapy have been under way at M. D. Anderson since 1995.

Then, working with John Minna, M.D., and other investigators from the University of Texas Southwestern Medical Center, the investigators found that parts of chromosome 3p (a region known as 3p21.3) are often missing in lung cells at the very beginning of cancer development. "One of two inherited copies of this chromosomal region is missing and we speculate this is a fragile site that breaks easily in response to exposure to cancer causing agents," says Roth. "This is a very early change that we see in stage one cancer, and carcinoma in situ. We also see it in the lung cells of smokers who do not have cancer."

The researchers found that area contains a number of tumor suppressor genes including FUS1 that not only inhibited tumor growth and metastasis, but induced human lung cancer cell death.

Still, people who have lost one copy of their FUS1 gene at 3p21.3 have an active copy on their intact chromosome, but for reasons unknown as yet, the now-described defect in myristoylation occurs, rendering the proteins produced by the remaining FUS1 gene functionally inactive. "Inactivation of FUS1 appears to be a two-hit process, in which one good FUS1 gene is lost, and the other produces tumor suppressor protein that is disabled," says Ji.

The gene therapy trial underway at M. D. Anderson may offer a solution, says Roth. It uses bubbles of fat to encase millions of copies of FUS1 genes, which can be easily absorbed into tumor cells. So far, six patients with metastatic lung cancer have been treated.

Although replacement of the FUS1 gene in tumor cells does not specifically repair myristoylation defects, Roth says that experiments suggest "overexpressing the gene somehow seems to overcomes this problem."

Replacing the FUS1 gene therapeutically at the earliest time possible in patients missing one copy of the 3p21.3 region "may possibly prevent or delay the development of lung tumors," Ji says.

The study was funded primarily by grants from the National Cancer Institute and the National Institutes of Health. Other co-authors include John Minna, M.D., and Masashi Kondo, from UT Southwestern Medical Center, and from M. D. Anderson: Futoshi Uno, M.D., Ph.D., Jiichiro Sasaki M.D., Ph.D., Masahiko Nishizaki M.D., Ph.D., Giovanni Carboni M.D., Kai Xu, and Edward Atkinson, Ph.D.