Deeper dive into emerging cancer drugs’ actions

| Written by Jessica Moore
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A major challenge in developing cancer drugs is finding ways to kill tumors without damaging healthy tissue. It’s tough—since cancer cells share the same cellular machinery as normal cells, scientists have to be mindful about the targets they choose. One way to balance these concerns is to target cellular processes—such as protein synthesis and degradation—that tumors frequently overuse to support their rapid and aberrant growth.

Unfortunately for cancer cells, this overproduction leads to a loss of quality—many of their proteins are malformed. These defective proteins often become tagged with a protein called ubiquitin that marks them for destruction by the proteasome.

A new class of chemotherapeutics, p97 inhibitors, exploits this vulnerability. p97 is an enzyme that moves defective proteins where they can then be readily destroyed by the proteasome. To achieve this, p97 interacts with many other proteins, most of which recognize the ubiquitin tag.

A new study, published in Cell Chemical Biology by Matthew Petroski, Ph.D., associate professor in the Tumor Initiation and Maintenance Program, provides key insights into how p97 inhibitors might fit into an overall cancer treatment strategy.

The results and what they mean “We discovered an ‘escape mechanism’ from a promising experimental drug,” said Petroski. “Cancer cells that can survive treatment have a mutation in the gene for p97 that lets it function even in the presence of the inhibitor.”

“This isn’t a death knell for these drugs—tumors can develop resistance to almost anything,” added Petroski. “It’s useful information—it means that patients whose cancer becomes insensitive to this compound might still respond to other drugs targeting the proteasome system, including other p97 inhibitors.”

His team’s investigation of how inhibition changes p97 identified a direct, rapid readout that can be used in the future to discover additional inhibitors of the enzyme.

“Only a subset of p97’s partner proteins are stuck to it when it’s inhibited,” explained Petroski. “This insight should help accelerate the development of this class of drugs.”

Next steps Petroski’s lab is now working with the Prebys Center for Chemical Genomics to find new p97 inhibitors, taking advantage of these observations. “Our hope is that we’ll ultimately find better drugs that provide prolonged benefit for cancer patients,” said Petroski.

The paper is available online here.

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Matthew Petroski