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Sanford-Burnham scientists unravel cancer drug's secret to resistance
Date:3/19/2012

lex network of enzymes tags proteins with a molecule called ubiquitin. Once it receives this "kiss of death," a protein is destined for the proteasome, the cell's "meat grinder." Depending on which proteins are being destroyed, this process helps control almost every aspect of cellular function and is frequently altered in cancer.

When MLN4924 shuts down NEDD8, a critical part of the ubiquitin proteasome system malfunctions and instead of continuing to proliferate, cancer cells die.

According to Petroski, finding new ways to target the ubiquitin proteasome system and prevent it from chewing up key proteins is a promising research area that might lead to powerful new anti-cancer therapeutics.

How cancer cells escape MLN4924

Petroski and his laboratory, including the study's first author, researcher Julia Toth, Ph.D., discovered that MLN4924 kills more than 99 percent of cancer cells in laboratory tests. Yet a small population survives.

In that small but important population of MLN4924-resistant cells, Petroski's team found a mutation in the NEDD8-activating enzyme. With just a single change in a single nucleotide in the gene that encodes this enzyme, the cells were able to survive.

"Gleevec and other cancer drugs that work by binding and inactivating kinasesanother class of enzymesalso lose their potency when their target proteins mutate. But this is the first time such a mechanism has been identified for a drug that targets an enzyme of the ubiquitin proteasome system," Petroski said.

Understanding how cancer cells manage to avoid death at the hands of MLN4924 provides clues as to how scientists might improve it or other drugs that target the ubiquitin proteasome system in a way that makes them more effective. In addition to further developing their laboratory test to determine a drug's efficacy, Petroski and his team are now leveraging this knowledge to find new anti-cancer drugsparticularly dr
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Contact: Heather Buschman, Ph.D.
hbuschman@sanfordburnham.org
858-795-5343
Sanford-Burnham Medical Research Institute
Source:Eurekalert  

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