Common genetic mutation key to why some tumors are resistant to radiation

Researchers have long known that many cancerous tumors, including prostate cancer, endometrial cancer, melanoma and certain aggressive brain tumors, have a genetic mutation capable of inactivating PTEN, a tumor suppressor. The PTEN gene produces a protein that is found in almost all tissues within the body. It is this protein that acts as a tumor suppressor by preventing cells from growing and dividing too rapidly. Those tumors with the PTEN mutation are often resistant to radiation therapy. The reason why has alluded scientists - until now.

Washington University School of Medicine researchers have solved this mystery, discovering that PTEN-deficient cells have "defective checkpoints." As they describe in an article to be published in the July 15, 2009 issue of Cell Cycle, cells go through several phases as they grow and divide, with checkpoints along the way that assess whether the cell is healthy enough to continue its work. Should the cell be damaged in some way, for example if there is damage to genetic material resulting from radiation treatments, checkpoint signals should alert the cell to wait until repairs are made. Or they should induce the cell to die.

For the first time, the researchers have shown that the checkpoints are affected in those cells with deficient PTEN, not that cells with PTEN mutations had defective DNA repair mechanisms, as previous research had suggested. According to Tej K. Pandita, Ph.D., a researcher with the Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital, and his colleagues, "DNA repair is independent of PTEN function in tumor cells grown in the laboratory, indicating that defective DNA repair is not the cause of the unstable genomes frequently seen in PTEN-deficient tumor cells and not the explanation for radiation resistance in these tumors."

The findings, says Dr. Pandita, indicate that in order to increase the sensitivity to radiation in tumors with PTEN mutations, new drugs will need to be developed that correct for faulty checkpoint processes. "The defective checkpoints contribute to radio-resistance," he explains. "When a cell gets damaged by radiation, normally checkpoints will make it stop growing to repair the damage. If the checkpoints are working but the cell has a defective DNA repair system, the cell will be radio-sensitive. But if the checkpoints don't operate, the cell can bypass DNA repair and continue to grow and divide. Then the cells are radio-resistant." 

News Release: Researchers find how a common genetic mutation makes cancer radiation resistant www.mednews.wustl.edu    June 8, 2009