Blocking a Single Kinase Kills Neuroblastoma Cells

Cancer researchers have identified an enzyme required for the growth of neuroblastoma cells and anticipate that drugs designed to block it will improve treatment for this often-fatal childhood cancer.

Investigators at the Children's Hospital of Philadelphia (Pennsylvania, USA) used small interfering RNA (siRNA) to perform a genetic screen that covered the entire neuroblastoma kinome, the collection of the cancer cell's kinase enzymes. Many kinases have been implicated in the growth and spread of various types of cancers.

Results published in the February 2, 2010, online edition of the journal Proceedings of the [US] National Academy of Sciences (PNAS) revealed that 30 kinases showed significant cellular cytotoxicity when depleted, with loss of the cell cycle checkpoint kinase 1 (CHK1/CHEK1) being the most potent. Neuroblastoma cells were sensitive to two CHK1 inhibitors SB21807 and TCS2312, and CHK1 inhibition caused apoptosis during the S-phase of the cell cycle.

"This screen was an unbiased study,” said senior author Dr. Kristina A. Cole, a pediatric oncologist at the Children's Hospital of Philadelphia. "We did not know beforehand which kinase would have the most potent effect. In fact, we would not have suspected CHK1, which was thought to be a tumor suppressor. It actually has the opposite effect in neuroblastoma. Its signals appear to drive neuroblastoma growth, likely by allowing them to tolerate stress to DNA caused by the MYC and MCYN oncogenes, which are active in neuroblastoma. Blocking CHK1 activity by RNA interference or by small-molecule inhibitors kills neuroblastoma cells.”

"Our study implicates this protein as a promising treatment target for high-risk neuroblastoma,” said Dr. Cole. "The fact that drugs acting on this protein are already being studied in clinical trials for adult cancers, may hasten the process of testing this treatment strategy in children. While it is compelling that there is single-agent activity in neuroblastoma, we anticipate that CHK1 inhibitors combined with chemotherapy will be significantly more potent.”

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