Faulty Checkpoints Cause Radiation Resistance in PTEN Mutant Tumors

Cancer researchers have identified the molecular mechanism that renders cancer cells with PTEN mutations resistant to radiation therapy.

PTEN (phosphatase and tensin homologue) acts as a tumor-suppressor gene through the action of its phosphatase protein product. This phosphatase is involved in the regulation of the cell cycle, preventing cells from growing and dividing too rapidly. Mutations of this gene contribute to the development of certain cancers. When the PTEN enzyme is functioning properly, it acts as part of a chemical pathway that signals cells to stop dividing and causes cells to undergo programmed cell death (apoptosis) when necessary. These functions prevent uncontrolled cell growth that can lead to the formation of tumors. There is also evidence that the protein made by the PTEN gene may play a role in both cell movement and adhesion of cells to surrounding tissues.

Tumors with PTEN mutations, such as prostate cancer, endometrial cancer, melanoma, and certain aggressive brain tumors, are often resistant to radiation therapy. The generally accepted explanation for this behavior has been that cells with mutant PTEN possessed malfunctioning DNA repair systems. Radiation treatment caused more DNA damage, but that cells with damaged DNA were still able to reproduce uncontrollably.

Results published in the July 15, 2009, online edition of the journal Cell Cycle suggest a different explanation. Investigators from Washington University School of Medicine (St. Louis, MO, USA) studied PTEN deficient cells growing in tissue culture. They found that DNA repair was independent of PTEN function, and that defective DNA repair was not the cause of unstable genomic structures, nor was it the explanation for radiation resistance in these tumors.

Instead, the investigators found that the underlying cause for radiation resistance was a defect in the cellular checkpoint mechanism that would normally channel abnormal cells into the apoptotic pathway. "The defective checkpoints contribute to radioresistance,” explained senior author Dr. Tej K. Pandita, associate professor of radiation oncology and genetics at the Washington University School of Medicine. "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 radiosensitive. But if the checkpoints do not operate, the cell can bypass DNA repair and continue to grow and divide. Then the cells are radioresistant.”

To increase radiation sensitivity in tumors with PTEN mutations it will be necessary to develop drugs that correct for the faulty checkpoint processes.

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Washington University School of Medicine