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Resistance is futile: Duke researchers fight chemotherapy drug resistance

<p>The Duke Cancer Center. The Duke researchers hope to shorten stays here by finding a way to curb chemotherapy resistance.</p>

The Duke Cancer Center. The Duke researchers hope to shorten stays here by finding a way to curb chemotherapy resistance.

Chemotherapy is ubiquitous in the world of cancer treatment, but cancer cells have a way to fight back: they simply resist the drugs used in the treatment. Acquired resistance to medication has been responsible for nearly 90% of cancer-related deaths. 

Researchers from Duke, MIT and the University of Rhode Island believe they have found a method to prevent this resistance from emerging.

“Tumor cells can be innately resistant to chemotherapeutic agents, or they can mutate or modify cellular processes to acquire resistance to drugs,” wrote the researchers in an email to the Chronicle. 

The team included four researchers from Duke: Professor of Chemistry Jiyong Hong; Professor of Biochemistry Pei Zhou; Javaria Najeeb, Graduate School ‘19; and Jessica Wojtaszek, Graduate School ‘15 and a research associate at the Duke School of Medicine. The four researchers mentioned that Jenny Xue, Trinity ‘14 and a co-author of the study, played a significant role in this search as an undergraduate. 

Chemotherapy drugs damage the DNA in cells to prevent it from replicating. Cancer cells grow and replicate rapidly, leaving them more vulnerable to DNA damage than healthy cells, so the drugs kill them while leaving most healthy cells intact. However, during a course of chemotherapy, some cancer cells may develop strategies to survive its effects.

In a recent study published in Cell, the researchers reported that they had discovered a molecule that inhibits translesion synthesis, a common DNA-repairing mechanism by which cancer cells develop drug resistance. Previous research has determined that a protein—Rev1—plays a crucial role in this process. 

The researchers ran tests on 10,000 different compounds to find a small molecule that could inhibit its function.

“High-throughput screens are an integral part of any drug-discovery campaign,” the researchers wrote. “We screened a large set of compounds with varying chemical properties and structures to identify a potent lead.” 

The high-throughput search ultimately identified a molecule JH-RE-06, which acts like a molecular glue, “[forcing] two Rev1 molecules to ‘stick’ together,” they wrote. When bound by the molecule, Rev1 proteins cannot help cancer cells resist chemotherapy drugs. 

So far the molecule has been tested in human cancer cell lines and mouse models of human melanoma—showing success in both—though researchers caution that they are still far away from clinical application. 

However, the researchers are optimistic that humans will one day benefit from this discovery. 

“If the compound works in humans as we predict, it will dramatically enhance the effectiveness of current chemotherapeutic drugs and suppress the occurrence of treatment-induced secondary tumors,” the researchers wrote. 

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