Inhibitor Molecule Effectively Kills Sarcomas

The small-molecular-weight inhibitor molecule MK 1775, which has been tested successfully as a treatment for several types of cancer, was found in a recent study to be equally effective against sarcomas.

MK-1775 is an inhibitor of Wee1, a kinase that phosphorylates CDC2 (cyclin dependent kinase 1 also known as Cdk1 or cell division control protein 2 homolog) to inactivate the CDC2/cyclin B complex (regulating the cell cycle G2 checkpoint). Since most human cancers harbor p53-dependent G1 checkpoint abnormalities, they are dependent on the G2 checkpoint. G2 checkpoint abrogation may therefore sensitize cancer cells lacking the p53 tumor suppressor gene to anticancer agents. In vivo, MK-1775 potentiated tumor growth inhibition by DNA-damaging chemotherapeutic agents such as gemcitabine, carboplatin, and cisplatin, and cotreatment did not significantly increase toxicity.

Investigators at the Moffitt Cancer Center (Tampa, FL, USA) examined the potential for MK 1755 treatment of sarcomas, a group of more than 70 different relatively rare cancers that are usually resistant to chemotherapy.

They reported in the November 14, 2011, online edition of the journal Molecular Cancer Therapeutics that MK1775 treatment at clinically relevant concentrations led to unscheduled entry into mitosis and initiation of apoptotic cell death in all sarcomas tested. The cytotoxic effect of Wee1 inhibition on sarcoma cells appeared to be independent of p53 status as all sarcoma cell lines with different p53 mutations were highly sensitive to MK1775 treatment. In patient-derived sarcoma samples MK1775 administered as a single agent caused significant apoptotic cell death.

“The cytotoxic effect of Wee1 inhibition on sarcoma cells appears to be independent of p53 mutation status following our testing sarcoma cell lines with different p53 mutations,” said senior author Dr. associate professor of experimental therapeutics at the Moffitt Cancer Center. “All of them were highly sensitive to MK1775, suggesting that Wee1 inhibition may represent a novel approach in the treatment of sarcomas.”

“There is a great need for new agents to treat sarcomas and improve patient outcomes,” said Dr. Altiok. “Toxicity from radiation and chemotherapy is high and response rates for patients with sarcomas are modest, with improvement and survival negligible. Inhibition of the pathways critical to tumor cell survival by molecularly targeted therapy represents an opportunity to reverse the biological basis of tumor formation. We found that MK1775 treatment induces apoptopic cell death in four sarcoma cell lines at clinically relevant doses.”

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