Potential New Drug Increases Cancer Sensitivity to Radiation Therapy

It phosphorylates several key proteins that initiate activation of the DNA damage checkpoint, leading to cell cycle arrest, DNA repair, or apoptosis. Several of these targets, including p53, CHK2, BRCA1, and H2AX are tumor suppressors.

A mutated, nonfunctional form of ATM causes the rare, inherited childhood disease ataxia-telangiectasia (A-T). A-T is a very complex disease, involving neuronal degeneration, immunodeficiency, extreme radiation sensitivity, and a striking predisposition to cancer.

Understanding the importance of the link between ATM and extreme sensitivity to ionizing radiation (IR), investigators at St. Jude Children's Research Hospital (Memphis, TN, USA) began a search for drug candidates that would block the activity of this gene or its product, ATM protein kinase, in cancer cells. They reported in the September 15, 2008, issue of the journal Cancer Research that screening of large number of compounds yielded a candidate drug called CP466722. This compound was nontoxic and did not inhibit phosphatidylinositol 3-kinase (PI3K) or PI3K-like protein kinase family members in cells. Studies in vitro demonstrated that irradiation activated ATM, which in turn triggered the normal cascade of biochemical events that repaired broken DNA, and that CP466722 inhibited all of these events. This condition was identical to what is seen in cells of children with A-T.

Removing CP466722 rapidly and completely reversed inhibition of cellular ATM kinase activity. Clonogenic survival assays showed that transient inhibition of ATM was sufficient to sensitize cells to IR, which suggests that therapeutic radiosensitization may only require ATM inhibition for short periods of time.

"Our ability to rapidly and reversibly regulate ATM activity with CP466722 also gives us a new tool to study the function of this protein, which plays such a critical role in the ability of both normal and cancerous cells to repair their DNA,” said first author Dr. Michael Rainey, an oncology researcher at St. Jude Children's Research Hospital. "This approach will help us learn more about the repair events triggered by ATM in response to DNA damage.”

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St. Jude Children's Research Hospital