As organisms adapt to their environment, adaptations that serve them in their current environment can become liabilities if that environment changes.

The control of traits that are an asset in one situation and a liability by the same gene is called antagonistic pleiotropy.

In the March 16, 2020, online issue of Nature Genetics, researchers reported a method to systematically identify mutations that conferred antagonistic pleiotropy – in the form of resistance to one drug, but heightened sensitivity to another – in acute myeloid leukemia (AML) cells.

They used their method to show that the sensitivity of AML cells to BET bromodomain inhibition and BCL-2 inhibition is an example of antagonistic pleiotropy.

Senior author Kris Wood told BioWorld that “the mechanisms that give resistance to [the bromodomain inhibitor] JQ-1 seem to frequently or maybe even always lead to a cellular sensitivity to ABT-199,” better known in the biopharma industry as Venclexta (venetoclax, Abbvie Inc.), which is approved for chronic lymphocytic leukemia as well as AML.

The relationship between JQ-1 and Venclexta did not cut both ways, and Wood said that “dual-directionality in drug resistance/sensitivity is actually not inherent to an AP relationship for a number of reasons… although we would expect that a significant fraction of cases would exhibit bidirectionality. {But] our current study is not designed to assess what this fraction would be.”

Beyond the specific relationship between JQ-1 and Venclexta, he said, the work shows that “resistance is both a problem and an opportunity.”

Wood is an assistant professor of pharmacology and cancer biology and biomedical engineering and a member of the Duke Cancer Institute, and co-corresponding author of the Nature Genetics paper.

The most typical way to deal with drug resistance, which is an all-but-inevitable feature of targeted therapies, is the design of second- and third-generation inhibitors that will be active against resistance mutations.

An alternate strategy could be to find the tradeoffs cells are making to gain resistance to a given drug, and use sequential drug regimens to first lure them into making those tradeoffs, and then exploiting the tradeoff to kill the cell.

Evolutionary traps are in some ways similar to the induction of a BRCA-like state to prime cells for sensitivity to PARP inhibitors.

BRCA mutations “give cancer cells an advantage during the phase of disease that involves tumor initiation and tumor progression, but they give cells a major disadvantage in the context of PARP inhibition,” Wood said.

Another example of antagonistic pleiotropy is proteins that act as oncogenes under some circumstances, but as tumor suppressors under others.

Wood’s laboratory has been focused on chemogenomic screens. The team uses CRISPR to find modifiers of drug treatment – genes that affected the sensitivity to a drug, for better or for worse.

Modifier profiles depend on a drug’s mechanism of action. Two drugs that work via the same mechanism, such as two mTOR inhibitors, will have largely the same modifiers, while drugs that affect different targets can have very different modifiers.

Within that larger context, the researchers began to wonder “whether we could identify scenarios where the genes that give resistance to one drug… give sensitization to another drug.”

The relationship between JQ-1 resistance and ABT-199 hypersensitivity showed that such relationships can indeed be identified. Wood said that he and his colleagues are planning to follow up on the translational possibilities of their findings, and have also identified another example of antagonistic pleiotropy that could be used to set an evolutionary trap.

More generally, Wood said, “this work points directly to ways that new studies could further understand what types of biological processes have the property of being beneficial in certain circumstances and deleterious in other circumstances, and why that is.”

“Where our work is the most novel is specifically in the context of applying these concepts to multiple drug treatments,” he said. “Evolutionary biologists have for years been thinking about concepts like the ones we were thinking about.”

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